Heterocyclic dihydropyrimidine compounds

ABSTRACT

Novel heterocyclic dihydropyrimidine compounds useful as inhibitors of potassium channel function (especially inhibitors of the K v 1 subfamily of voltage gated K +  channels, especially inhibitors K v 1.5 which has been linked to the ultra-rapidly activating delayed rectifier K +  current I Kur ), methods of using such compounds in the prevention and treatment of arrhythmia and I Kur -associated conditions, and pharmaceutical compositions containing such compounds.

This application is a Divisional Application of prior application Ser.No. 10/660,878 filed on Sep. 12, 2003, which is a Divisional Applicationof U.S. application Ser. No. 09/729,731 filed Dec. 5, 2000, which issuedas U.S. Pat. No. 6,706,720 on Mar. 16, 2004, which claims priority toU.S. Provisional application Ser. No. 60/236,037 filed Sep. 28, 2000 andU.S. Provisional application Ser. No. 60/169,091 filed Dec. 6, 1999. Theentirety of each of these applications is incorporated herein byreference.

FIELD OF THE INVENTION

The present invention provides for heterocyclic dihydropyrimidinecompounds useful as inhibitors of potassium channel function (especiallyinhibitors of the K_(v)1 subfamily of voltage gated K⁺ channels, moreespecially inhibitors K_(v)1.5 which has been linked to theultra-rapidly activating delayed rectifier K⁺ current I_(Kur)) and topharmaceutical compositions containing such compounds. The presentinvention further provides for methods of using such compounds in thetreatment of arrhythmia, I_(Kur)-associated disorders, and otherdisorders mediated by ion channel function.

BACKGROUND OF THE INVENTION

The importance of potassium channels was first recognized approximatelyfifty years ago when Hodgkin and Huxley discovered that potassium ionscontributed to the current that excited the squid giant axon. Researchin the area, however, was hampered by the lack of selective, highaffinity ligands for potassium channels. But the advent of recombinantDNA techniques and single cell and whole cell voltage clamp techniqueshas changed the slow pace of the field. Indeed, potassium channels thatexhibit functional, pharmacological and tissue distributioncharacteristics have been cloned. These cloned potassium channels areuseful targets in assays for identifying candidate compounds for thetreatment of various disease states. Potassium channels have turned outto be the most diverse family of ion channels discovered to date. Theymodulate a number of cellular events such as muscle contraction,neuro-endocrine secretion, frequency and duration of action potentials,electrolyte homeostatis, and resting membrane potential.

Potassium channels are expressed in eukaryotic and procaryotic cells andare elements in the control of electrical and non-electrical cellularfunctions. Potassium channels have been classified according to theirbiophysical and pharmacological characteristics. Subclasses of thesechannels have been named based on amino acid sequence and functionalproperties. Salient among these are the voltage dependent potassiumchannels, for example voltage gated potassium channels (e.g., K_(v)1,K_(v)2, K_(v)3, K_(v)4). Subtypes within these subclasses have beencharacterized as to their putative function, pharmacology anddistribution in cells and tissues (Chandy and Gutman, “Voltage-gatedpotassium channel genes” in Handbook of Receptors and Channels—Ligandand Voltage-gated Ion Channels, ed. R. A. North, 1995; Doupnik et al.,Curr. Opin. Neurobiol. 5:268, 1995). For example, the K_(v)1 class ofpotassium channels is further subdivided depending on the molecularsequence of the channel, for example K_(v)1.1, K_(v)1.2, K_(v)1.3,K_(v)1.4, K_(v)1.5, K_(v)1.6, and K_(v)1.7. Functional voltage-gated K⁺channels can exist as multimeric structures formed by the association ofeither identical or dissimilar subunits. This phenomena is thought toaccount for the wide diversity of K⁺ channels. However, subunitcompositions of native K⁺ channels and the physiologic role thatparticular channels play are, in most cases, still unclear.

Membrane depolarization by K_(v)1.3 inhibition has been shown to be aneffective method to prevent T-cell proliferation and therefore hasapplications in many autoimmune conditions. Inhibition of K⁺ channels inthe plasma membrane of human T-lymphocytes has been postulated to play arole in eliciting immunosuppressive responses by regulatingintracellular Ca⁺⁺ homeostasis, which has been found to be important inT-cell activation.

The K_(v)1.3 voltage-gated potassium channel is found in neurons, bloodcells, osteoclasts and T-lymphocytes. The Chandy and Cahalanlaboratories proposed a hypothesis that blocking the K_(v)1.3 channelwould elicit an immunosuppressant response. (Chandy et al., J. Exp. Med.160, 369, 1984; Decoursey et al., Nature, 307, 465, 1984). However, theK⁺ channel blockers employed in their studies were non-selective. Untilresearch with the peptide margatoxin, a peptide found in scorpion venom,no specific inhibitor of the K_(v)1.3 channel existed to test thishypothesis. Although a laboratory (Price et al., Proc. Natl, Acad, Sci.USA, 86, 10171, 1989) showed that charybdotoxin would block K_(v)1.3 inhuman T-cells, charybdotoxin was subsequently shown to inhibit fourdifferent K⁺ channels (K_(v)1.3 and three distinct small conductanceCa⁺⁺ activated K⁺ channels) in human T-lymphocytes, limiting the use ofthis toxin as a probe for the physiological role of K_(v)1.3 (Leonard etal., Proc. Natl, Acad. Sci, USA, 89, 10094, 1992). Margatoxin, on theother hand, blocks only K_(v)1.3 in T-cells, and has immunosuppressantactivity on both in in vitro and in vivo models. (Lin et al., J. exp.Med, 177, 637, 1993). The therapeutic utility of this compound, however,is limited by its potent toxicity. Recently, a class of compounds hasbeen reported that may be an attractive alternative to the abovementioned drugs, see for example U.S. Pat. Nos. 5,670,504; 5,631,282;5,696,156; 5,679,705; and 5,696,156. While addressing some of theactivity/toxicity problems of previous drugs, these compounds tend to beof large molecular weight and are generally produced by syntheticmanipulation of a natural product, isolation of which is cumbersome andlabor intensive.

Immunoregulatory abnormalities have been shown to exist in a widevariety of autoimmune and chronic inflammatory diseases, includingsystemic lupus erythematosis, chronic rheumatoid arthritis, type I andII diabetes mellitus, inflammatory bowel disease, biliary cirrhosis,uveitis, multiple sclerosis and other disorders such as Crohn's disease,ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis,ichthyosis, Graves ophthalmopathy and asthma.

Although the underlying pathogenesis of each of these conditions may bequite different, they have in common the appearance of a variety ofauto-antibodies and self-reactive lymphocytes. Such self-reactivity maybe due, in part, to a loss of the homeostatic controls under which thenormal immune system operates. Similarly, following a bone-marrow or anorgan transplantation, the host lymphocytes recognize the foreign tissueantigens and begin to produce antibodies which lead to graft rejection.

One end result of an autoimmune or a rejection process is tissuedestruction caused by inflammatory cells and the mediators they release.Anti-inflammatory agents such as NSAID's act principally by blocking theeffect or secretion of these mediators but do nothing to modify theimmunologic basis of the disease. On the other hand, cytotoxic agents,such as cyclophosphamide, act in such a nonspecific fashion that boththe normal and autoimmune responses are shut off. Indeed, patientstreated with such nonspecific immunosuppressive agents are as likely tosuccumb from infection as they are from their autoimmune disease.

Cyclosporin A (CsA), which was approved by the US FDA in 1983 iscurrently the leading drug used to prevent rejection of transplantedorgans. In 1993, FK-506 (Prograf) was approved by the US FDA for theprevention of rejection in liver transplantation. CsA and FK-506 act byinhibiting the body's immune system from mobilizing its vast arsenal ofnatural protecting agents to reject the transplant's foreign protein. In1994, CsA was approved by the US FDA for the treatment of severepsoriasis and has been approved by European regulatory agencies for thetreatment of atopic dermatitis. Though they are effective in fightingtransplant rejection, CsA and FK-506 are known to cause severalundesirable side effects including nephrotoxicity, neurotoxicity, andgastrointestinal discomfort. Therefore, a selective immunosuppressantwithout these side effects still remains to be developed. Potassiumchannel inhibitors promise to be the solution to this problem.

Atrial fibrillation (AF) and atrial flutter are the most common cardiacarrhythmias in clinical practice and are likely to increase inprevalence with the aging of the population. Currently, AF affects morethan 1 million Americans annually, represents over 5% of all admissionsfor cardiovascular diseases and causes more than 80,000 strokes eachyear in the United States. While AF is rarely a lethal arrhythmia, it isresponsible for substantial morbidity and can lead to complications suchas the development of congestive heart failure or thromboembolism.Currently available Class I and Class III antiarrhythmic drugs reducethe rate of recurrence of AF, but are of limited use because of avariety of potentially adverse effects including ventricularproarrhythmia. Because current therapy is inadequate and fraught withside effects, there is a clear need to develop new therapeuticapproaches

Antiarrhythmic agents of Class III are drugs that cause a selectiveprolongation of the duration of the action potential without significantcardiac depression. Available drugs in this class are limited in number.Examples such as sotalol and amiodarone have been shown to possessinteresting Class III properties (Singh B. N., Vaughan Williams E. M. “AThird Class of Anti-Arrhythmic Action: Effects On Atrial And VentricularIntracellular Potentials And Other Pharmacological Actions On CardiacMuscle, of MJ 1999 and AH 3747” Br. J. Pharmacol 1970; 39:675-689. andSingh B. N., Vaughan Williams E. M, “The Effect of Amiodarone, A NewAnti-Anginal Drug, On Cardiac Muscle”, Br J. Pharmacol 1970;39:657-667), but these are not selective Class III agents. Sotalol alsopossesses Class II effects which may cause cardiac depression and iscontraindicated in certain susceptible patients. Amiodarone, also is nota selective Class III antiarrhythmic agent because it possesses multipleelectrophysiological actions and is severely limited by side effects(Nademanee, K. “The Amiodarone Odessey”. J. Am. Coll. Cardiol.1992;20:1063-1065.) Drugs of this class are expected to be effective inpreventing ventricular fibrillation. Selective class III agents, bydefinition, are not considered to cause myocardial depression or aninduction of arrhythmias due to inhibition of conduction of the actionpotential as seen with Class I antiarrhythmic agents.

Class III agents increase myocardial refractoriness via a prolongationof cardiac action potential duration. Theoretically, prolongation of thecardiac action potential can be achieved by enhancing inward currents(i.e. Na⁺ or Ca²⁺ currents; hereinafter I_(Na) and I_(Ca), respectively)or by reducing outward repolarizing potassium (K⁺) currents. The delayedrectifier (I_(K)) K⁺ current is the main outward current involved in theoverall repolarization process during the action potential plateau,whereas the transient outward (I_(to)) and inward rectifier (I_(KI)) K⁺currents are responsible for the rapid initial and terminal phases ofrepolarization, respectively. Cellular electrophysiologic studies havedemonstrated that I_(K) consists of two pharmacologically andkinetically distinct K⁺ current subtypes, I_(Kr) (rapidly activating anddeactivating) and I_(Ks) (slowly activating and deactivating)(Sanguinetti and Jurkiewicz, Two Components Of Cardiac Delayed RectifierK⁺ Current: Differential Sensitivity To Block By Class IIIAntiarrhythmic Agents, J Gen Physiol 1990, 96:195-215). Class IIIantiarrhythmic agents currently in development, including d-sotalol,dofetilide (UK-68,798), almokalant (H234/09), E-4031 andmethanesulfonamide-N-[1′-6-cyano-1,2,3,4-tetrahydro-2-naphthalenyl)-3,4-dihydro-4-hydroxyspiro[2H-1-benzopyran-2,4′-piperidin]-6yl]monochloride,predominantly, if not exclusively, block I_(Kr). Although, amiodarone isa blocker of I_(Ks) (Balser J. R. Bennett, P. B., Hondeghem, L. M. andRoden, D. M. “Suppression Of Time-Dependent Outward Current In GuineaPig Ventricular Myocytes: Actions Of Quinidine And Amiodarone. Circ.Res. 1991, 69:519-529), it also blocks I_(Na) and I_(Ca), effectsthyroid function, is as a nonspecific adrenergic blocker, and acts as aninhibitor of the enzyme phospholipase (Nademanee, K. “The AmiodaroneOdessey”. J. Am. Coll. Cardiol. 1992;20:1063-1065). Therefore its methodof treating arrhythmia is uncertain. Most Class III agents that areknown to be in development predominantly block I_(Kr).

Reentrant excitation (reentry) has been shown to be a prominentmechanism underlying supraventricular arrhythmias in man. Reentrantexcitation requires a critical balance between slow conduction velocityand sufficiently brief refractory periods to allow for the initiationand maintenance of multiple reentry circuits to coexist simultaneouslyand sustain AF. Increasing myocardial refractoriness by prolongingaction potential duration (APD), prevents and/or terminates reentrantarrhythmias. Most selective Class III antiarrhythmic agents currently indevelopment, such as d-sotalol and dofetilide predominantly, if notexclusively, block I_(kr), the rapidly activating component of I_(K)found both in the human atrium and ventricle.

Since these I_(kr) blockers increase APD and refractoriness both inatria and ventricle without affecting conduction per se, theoreticallythey represent potential useful agents for the treatment of arrhythmiaslike AF. These agents have a liability in that they have an enhancedrisk of proarrhythmia at slow heart rates. For example, torsades depoints has been observed when these compounds are utilized (Roden, D. M.“Current Status of Class III Antiarrhythmic Drug Therapy”, Am J.Cardiol, 1993; 72:44B-49B). This exaggerated effect at slow heart rateshas been termed “reverse frequency-dependence”, and is in contrast tofrequency-independent or frequency-dependent actions (Hondeghem, L. M.“Development of Class III Antiarrhythmic Agents”. J. Cadiovasc. Cardiol.20 (Suppl.2):S17-S22).

The slowly activating component of the delayed rectifier (I_(ks))potentially overcomes some of the limitations of I_(kr) blockersassociated with ventricular arrhythmias. Because of its slow activationkinetics however, the role of I_(ks) in atrial repolarization may belimited due to the relatively short APD of the atrium. Consequently,although I_(ks) blockers may provide distinct advantage in the case ofventricular arrhythmias, their ability to affect SVT is considered to beminimal.

The ultra-rapidly activating delayed rectifier K⁺ current (I_(kur)) isbelieved to represent the native counterpart to a cloned potassiumchannel designated K_(v)1.5 and, while present in human atrium, itappears to be absent in human ventricle. Furthermore, because of itsrapidity of activation and limited slow inactivation, I_(kur) isbelieved to contribute significantly to repolarization in human atrium.Consequently, a specific blocker of I_(kur), that is a compound whichblocks K_(v)1.5, would overcome the short coming of other compounds byprolonging refractoriness by retarding repolarization in the humanatrium without causing the delays in ventricular repolarization thatunderlie arrhythmogenic after depolarizations and acquired long QTsyndrome observed during treatment with current Class III drugs.

In intact human atrial myocytes an ultra-rapidly activating delayedrectifier K⁺ current I_(kur) which is also known as the sustainedoutward current, I_(sus) or I_(so), has been identified and this currenthas properties and kinetics identical to those expressed by the human K⁺channel clone (hK_(v)1.5, HK2) when isolated from human heart and stablyexpressed in human (HEK-293) cell lines. (Wang et al., 1993, Circ Res73:1061-1076; Fedida et al., 1993, Circ Res 73:210-216; Snyders et al.,1993, J Gen Physiol 101:513-543) and originally cloned from rat brain(Swanson et al., 10, Neuron 4:929-939). Although various antiarrythmicagents are now available on the market, those having both satisfactoryefficacy and a high margin of safety have not been obtained. Forexample, antiarrythmic agents of Class I according to the classificationscheme of Vaughan-Williams (“Classification Of Antiarrhythmic Drugs: In:Cardiac Arrhythmias, edited by: E. Sandoe, E. Flensted-Jensen, K.Olesen; Sweden, Astra, Sodertalje, pp449-472, 1981) which cause aselective inhibition of the maximum velocity of the upstroke of theaction potential (_(max)) are inadequate for preventing ventricularfibrillation. In addition, they have problems regarding safety, namely,they cause a depression of myocardial contractility and have a tendencyto induce arrhythmias due to an inhibition of impulse conduction.Beta-adrenoceptor blockers and calcium antagonists which belong to ClassII and IV, respectively, have a defect in that their effects are eitherlimited to a certain type of arrhythmia or are contraindicated becauseof their cardiac depressant properties in certain patients withcardiovascular disease. Their safety, however, is higher than that ofthe antiarrhythmic agents of Class I.

SUMMARY OF THE INVENTION

The present invention provides heterocyclic dihydropyrimidine compoundsof the following formula I, including enantiomers, diastereomers, andsalts thereof, useful as inhibitors of potassium channel function(especially inhibitors of the K_(v)1 subfamily of voltage gated K⁺channels, more especially inhibitors K_(v)1.5 which has been linked tothe ultra-rapidly activating delayed rectifier K⁺ current I_(Kur)) forthe treatment of disorders such as arrhythmia and I_(Kur)-associateddisorders:

where

-   X¹, X² and X³ are independently selected from N, NR⁶, (CR⁷)_(q),    (CHR⁷)_(q), or C═O, wherein the bonds connecting X¹, X² and X³ to    adjacent atoms may be single or double bonds forming a 5 to    7-membered saturated, partially unsaturated or aromatic ring;-   R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are the same or different and are    independently selected from groups of the formula    —(CH₂)_(n)-(Z¹)_(m)-(CH₂)_(p)-Z²; or-   R¹, R², R³, R⁴ and R⁵ may, in one or more pairs of two (such as R¹    and R², R¹ and R³, R² and R³, R³ and R⁴ or R⁴ and R⁵), together with    the atoms to which they are bonded, form a carbocyclic, substituted    carbocyclic, heterocyclic or substituted heterocyclic group; or-   R⁶ and R⁷ may, in one or more pairs of two (such as R⁶ and R⁷, R⁶    and R⁶, or R⁷ and R⁷), together with the atoms to which they are    bonded, form a carbocyclic, substituted carbocyclic, heterocyclic or    substituted heterocyclic group;-   Z¹ is —CZ³Z⁴-, —O—, —NZ³-, —S—, —SO—, —SO₂—, —C(O)—, —C(O)Z³-,    —C(O)NZ⁴-, —C(S)—, —C(═NOZ³)-, alkyl, substituted alkyl, alkenyl,    substituted alkenyl, alkynyl, substituted alkynyl, carbocyclo,    substituted carbocyclo, aryl, substituted aryl, heterocyclo, or    substituted heterocyclo;-   Z² is hydrogen, —OZ⁵, —OC(O)Z⁵, —NZ⁵-C(O)-Z⁶, —NZ⁵-CO₂-Z⁶,    —NZ⁵(C═O)—NZ⁶Z⁷, —NZ⁵Z⁶, —NO₂, halo, —CN, —C(O)Z⁵, —CO₂Z⁵, —C(S)Z⁵,    —(C═NOZ⁵)Z⁶, —C(O)NZ⁵Z⁶, —C(S)NZ⁵Z⁶, —SZ⁵, —SOZ⁵, —SO₂Z⁵, —SO₂NZ⁵Z⁶,    alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,    substituted alkynyl, carbocyclo, substituted carbocyclo, aryl,    substituted aryl, heterocyclo (such as heteroaryl), or substituted    heterocyclo;-   Z³, Z⁴, Z⁵, Z⁶ and Z⁷ are independently hydrogen, halo, alkyl,    substituted alkyl, alkenyl, substituted alkenyl, alkynyl,    substituted alkynyl, carbocyclo, substituted carbocyclo, aryl,    substituted aryl, heterocyclo, or substituted heterocyclo; or-   Z³, Z⁴, Z⁵, Z⁶ and Z⁷ may, in one or more pairs of two (such as Z³    and Z⁴, Z⁵ and Z⁶ or Z⁶ and Z⁷), together with the atoms to which    they are bonded, form a carbocyclic, substituted carbocyclic,    heterocyclic or substituted heterocyclic group;-   n and p are independently selected from integers from 0 to 10    wherein, when m is 0, p is also 0;-   m is an integer selected from 0 or 1; and-   q is an integer selected from 1 to 3.

The present invention provides novel methods for the prevention andtreatment of arrhythmia and I_(Kur)-associated disorders employing oneor more compounds of the formula I, enantiomers, diastereomers orpharmaceutically acceptable salts thereof. In particular the presentinvention provides a novel method for the selective prevention andtreatment of supraventricular arrhythmias.

In addition, compounds within the formula I, as well as enantiomers,diastereomers and salts thereof are novel compounds, including compoundsof formula I* and salts thereof:

where

-   -   X¹, X², X³, R¹, R², R⁴ and R⁵ are as defined above;    -   R³* is —OZ⁵, —OC(O)-Z⁵, —NZ⁵-C(O)₂-Z⁶, —NZ⁵(C═O)—NZ⁶Z⁷, —NZ⁵Z⁶,        —(C═NOZ⁵)Z⁶, —C(O)NZ⁵*Z⁶*, —C(S)NZ⁵*Z⁶*, —SZ⁵, —SOZ⁵, —SO²Z⁵,        —SO₂NZ⁵Z⁶, —C(o)Z³*-Z²*, halo, alkyl, substituted alkyl,        alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,        carbocyclo, substituted carbocyclo, aryl, substituted aryl,        heterocyclo or substituted heterocyclo;    -   Z²* is other than hydrogen when Z³* is heterocyclo;    -   Z³* is heterocyclo or substituted heterocyclo;    -   Z⁵* is substituted alkyl, alkenyl, substituted alkenyl, alkynyl,        substituted alkynyl, carbocyclo, substituted carbocyclo, aryl,        substituted aryl, heterocyclo, or substituted heterocyclo; and    -   Z⁶* is hydrogen, alkyl, substituted alkyl, alkenyl, substituted        alkenyl, alkynyl, substituted alkynyl, carbocyclo, substituted        carbocyclo, aryl, substituted aryl, heterocyclo, or substituted        heterocyclo, provided that Z^(6*) is not hydrogen when Z^(5*) is        unsubstituted cycloalkyl, unsubstituted aryl, or unsubstituted        benzyl;    -   or Z⁵* and Z⁶* may together with the nitrogen atom to which they        are bonded form a heterocyclic group or substituted heterocyclic        group, provided that Z⁵* and Z⁶* do not together form        unsubstituted piperidinyl, unsubstituted pyrrolidinyl, or        unsubstituted morpholinyl, and further provided that when        -   (i) R¹ and R⁵ are each hydrogen; and        -   (ii) R² is aryl or substituted aryl; and        -   (iii) R⁴ is heterocyclo-substituted aryl; and        -   (iv) X¹, X² and X³ form the ring            where R⁷* is H or alkyl    -   Z⁵* and Z⁶* do not together form unsubstituted piperazinyl or        N-alkyl-substituted piperazinyl;

Preferred Compounds

Compounds of the formula I and salts thereof wherein one or more, andespecially all, of X¹, X², X³, R¹, R², R³, R⁴ and R⁵ are selected fromthe following definitions, are preferred compounds of the presentinvention:

-   R¹ is hydrogen;-   R² is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,    heterocyclo, substituted heterocyclo, carbocyclo or substituted    carbocyclo;-   R³ is —CH₂)_(n)-Z², —(CH₂)_(n)—C(O)Z³-(CH₂)_(p)-Z², or    —(CH₂)_(n)—C(O)NZ⁴-(CH₂)_(p)-Z;-   R⁴ is alkyl or substituted alkyl; and-   R⁵ is hydrogen, or —CH₂)_(n)-Z²; and-   X¹, X² and X³, together with the atoms to which they are bonded,    form a ring selected from:    where R⁶ and/or R⁷ are the same or different, as defined above.

Compounds of the formula I and salts thereof wherein one or more, andespecially all, of X¹, X², X³, R¹, R², R³, R⁴ and R⁵ are selected fromthe following definitions, are more preferred compounds of the presentinvention:

-   R¹ is hydrogen;-   R² is aryl (especially where aryl is phenyl), substituted aryl,    heterocyclo, substituted heterocyclo, carbocyclo or substituted    carbocyclo;-   R³ is —(CH₂)_(n)-Z², —(CH₂)_(n)—C(O)Z³-(CH₂)_(p)-Z², or    —(CH₂)_(n)—C(O)NZ⁴-(CH₂)_(p)-Z² wherein    -   Z² is selected from —C(O)NZ⁵Z⁶, —CO₂Z⁵, —SO₂Z⁵, —NZ⁵Z⁶,        —NZ⁵CO₂Z⁶, —NZ⁵C(O)Z⁶, —OZ⁵, aryl, substituted aryl,        heterocyclo, substituted heterocyclo, alkyl or substituted        alkyl;    -   Z³ is heterocyclo or substituted heterocyclo; and    -   n and p are independently selected from integers 0 to 3;-   R⁴ is alkyl, or substituted alkyl;-   R⁵ is hydrogen, or —(CH₂)_(n)-Z² wherein Z² is selected from    —C(O)NZ⁵Z⁶, —CO₂Z⁵, —NZ⁵Z⁶, aryl, substituted aryl, alkyl, or    substituted alkyl; and-   X¹, X² and X³, together with the atoms to which they are bonded,    form a ring selected from:

Compounds of the formula I and salts thereof wherein one or more, andespecially all, of X¹, X², X³, R¹, R², R³, R⁴ and R⁵ are selected fromthe following definitions, are most preferred compounds of the presentinvention:

-   R¹ is hydrogen;-   R² is aryl (especially where aryl is phenyl), substituted aryl,    heterocyclo, substituted heterocyclo, carbocyclo or substituted    carbocyclo;-   R³ is heterocyclo or substituted heterocyclo, —C(O)NZ⁵Z⁶,    —C(O)Z³-CONZ⁵Z⁶, —C(O)Z³-Z², or —C(O)Z³-CO₂Z⁵, wherein Z³ is    heterocyclo or substituted heterocyclo, and Z² is aryl or    substituted aryl;-   R⁴ is alkyl (especially lower alkyl) or substituted alkyl    (especially halo-substituted alkyl or alkoxy-substituted alkyl);-   R⁵ is hydrogen, alkyl or substituted alkyl; and-   X¹, X² and X³, together with the atoms to which they are bonded,    form a ring selected from:    wherein    -   R⁶ is H or C(O)Z⁵, where Z⁵ is alkyl or carbocyclo; and    -   R⁷ is independently selected from H, alkyl, substituted alkyl        (especially halo-substituted), halo, or CN

DETAILED DESCRIPTION OF THE INVENTION

The following are definitions of terms used in this specification. Theinitial definition provided for a group or term herein applies to thatgroup or term throughout the present specification, individually or aspart of another group, unless otherwise indicated.

The terms “alk” or “alkyl” refer to straight or branched chainhydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 8 carbonatoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,t-butyl, pentyl, hexyl, heptyl, octyl, etc. Lower alkyl groups, that is,alkyl groups of 1 to 6 carbon atoms, are generally most preferred. Theterm “substituted alkyl” refers to alkyl groups substituted with one ormore groups (such as by groups described above in the definition of R¹),preferably selected from aryl, substituted aryl, heterocyclo,substituted heterocyclo, carbocyclo, substituted carbocyclo, halo,hydroxy, alkoxy (optionally substituted), aryloxy (optionallysubstituted), alkylester (optionally substituted), arylester (optionallysubstituted), alkanoyl (optionally substituted), aryol (optionallysubstituted), cyano, nitro, amino, substituted amino, amido, lactam,urea, urethane, sulfonyl, etc.

The term “alkenyl” refers to straight or branched chain hydrocarbongroups having 2 to 12 carbon atoms, preferably 2 to 4 carbon atoms, andat least one double carbon to carbon bond (either cis or trans), such asethenyl. The term “substituted alkenyl” refers to alkenyl groupssubstituted with one or more groups (such as by groups described abovein the definition of R¹), preferably selected from aryl, substitutedaryl, heterocyclo, substituted heterocyclo, carbocyclo, substitutedcarbocyclo, halo, hydroxy, alkoxy (optionally substituted), aryloxy(optionally substituted), alkylester (optionally substituted), arylester(optionally substituted), alkanoyl (optionally substituted), aryol(optionally substituted), cyano, nitro, amino, substituted amino, amido,lactam, urea, urethane, sulfonyl, etc.

The term “alkynyl” refers to straight or branched chain hydrocarbongroups having 2 to 12 carbon atoms, preferably 2 to 4 carbon atoms, andat least one triple carbon to carbon bond, such as ethynyl. The term“substituted alkynyl” refers to alkynyl groups substituted with one ormore groups (such as by groups described above in the definition of R¹),preferably selected from aryl, substituted aryl, heterocyclo,substituted heterocyclo, carbocyclo, substituted carbocyclo, halo,hydroxy, alkoxy (optionally substituted), aryloxy (optionallysubstituted), alkylester (optionally substituted), arylester (optionallysubstituted), alkanoyl (optionally substituted), aryol (optionallysubstituted), cyano, nitro, amino, substituted amino, amido, lactam,urea, urethane, sulfonyl, etc.

The terms “ar” or “aryl” refer to aromatic homocyclic (i.e.,hydrocarbon) mono-, bi- or tricyclic ring-containing groups preferablyhaving 6 to 12 members such as phenyl, naphthyl and biphenyl. Phenyl isa preferred aryl group. The term “substituted aryl” refers to arylgroups substituted with one or more groups (such as by groups describedabove in the definition of R¹), preferably selected from alkyl,substituted alkyl, alkenyl (optionally substituted), aryl (optionallysubstituted), heterocyclo (optionally substituted), halo, hydroxy,alkoxy (optionally substituted), aryloxy (optionally substituted),alkanoyl (optionally substituted), aroyl, (optionally substituted),alkylester (optionally substituted), arylester (optionally substituted),cyano, nitro, amino, substituted amino, amido, lactam, urea, urethane,sulfonyl, etc., where optionally one or more pair of substituentstogether with the atoms to which they are bonded form a 3 to 7 memberring.

The terms “cycloalkyl” and “cycloalkenyl” refer to mono-, bi- or trihomocylcic ring groups of 3 to 15 carbon atoms which are, respectively,fully saturated and partially unsaturated. The term “cycloalkenyl”includes bi- and tricyclic ring systems that are not aromatic as awhole, but contain aromatic portions (e.g. fluorene,tetrahydronapthalene, dihydroindene, and the like). The rings ofmulti-ring cycloalkyl groups may be either fused, bridged and/or joinedthrough one or more spiro unions. The terms “substituted cycloalkyl” and“substituted cycloalkenyl” refer, respectively, to cycloalkyl andcycloalkenyl groups substituted with one or more groups (such as bygroups described above in the definition of R¹), preferably selectedfrom aryl, substituted aryl, heterocyclo, substituted heterocyclo,carbocyclo, substituted carbocyclo, halo, hydroxy, alkoxy (optionallysubstituted), aryloxy (optionally substituted), alkylester (optionallysubstituted), arylester (optionally substituted), alkanoyl (optionallysubstituted), aryol (optionally substituted), cyano, nitro, amino,substituted amino, amido, lactam, urea, urethane, sulfonyl, etc.

The terms “carbocyclo”, “carbocyclic” or “carbocyclic group” refer toboth cycloalkyl and cycloalkenyl groups. The terms “substitutedcarbocyclo”, “substituted carbocyclic” or “substituted carbocyclicgroup” refer to carbocyclo or carbocyclic groups substituted with one ormore groups as described in the definition of cycloalkyl andcycloalkenyl.

The terms “halogen” and “halo” refer to fluorine, chlorine, bromine andiodine.

The terms “heterocycle”, “heterocyclic”, “heterocyclic group” or“heterocyclo” refer to fully saturated or partially or completelyunsaturated, including aromatic (“heteroaryl”) or nonaromatic cyclicgroups (for example, 3 to 13 member monocyclic, 7 to 17 member bicyclic,or 10 to 20 member tricyclic ring systems, preferably containing a totalof 3 to 10 ring atoms) which have at least one heteroatom in at leastone carbon atom-containing ring. Each ring of the heterocyclic groupcontaining a heteroatom may have 1, 2, 3 or 4 heteroatoms selected fromnitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen andsulfur heteroatoms may optionally be oxidized and the nitrogenheteroatoms may optionally be quaternized. The heterocyclic group may beattached at any heteroatom or carbon atom of the ring or ring system.The rings of multi-ring heterocycles may be either fused, bridged and/orjoined through one or more spiro unions.

Exemplary monocyclic heterocyclic groups include azetidinyl,pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl,imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl,isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl,isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl,piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrahydropyranyl,tetrazoyl, triazolyl, morpholinyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane andtetrahydro-1,1-dioxothienyl,

and the like.

Exemplary bicyclic heterocyclic groups include indolyl, benzothiazolyl,benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl,tetra-hydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,indolizinyl, benzofuryl, benzofuranly, dihydrobenzofuranyl, chromonyl,coumarinyl, benzodioxolyl, dihydrobenzodioxolyl, benzodioxinyl,cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (suchas furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl),dihydroisoindolyl, dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl), tetrahydroquinolinyl, azabicycloalkyls(such as 6-azabicyclo[3.2.1]octane), azaspiroalkyls (such as 1,4dioxa-8-azaspiro[4.5]decane), imidazopyridinyl (such asimidazo[1,5-a]pyridin-3-yl), triazolopyridinyl (such as1,2,4-triazolo[4,3-a]pyridin-3-yl), and hexahydroimidazopyridinyl (suchas 1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyridin-3-yl),

and the like.

Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl,phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.

The terms “substituted heterocycle”, “substituted heterocyclic”,“substituted heterocyclic group” and “substituted heterocyclo” refer toheterocycle, heterocyclic and heterocyclo groups substituted with one ormore groups (such as by groups described above in the definition of R¹),preferably selected from alkyl, substituted alkyl, alkenyl, oxo, aryl,substituted aryl, heterocyclo, substituted heterocyclo, carbocyclo(optionally substituted), halo, hydroxy, alkoxy (optionallysubstituted), aryloxy (optionally substituted), alkanoyl (optionallysubstituted), aroyl (optionally substituted), alkylester (optionallysubstituted), arylester (optionally substituted), cyano, nitro, amido,amino, substituted amino, lactam, urea, urethane, sulfonyl, etc., whereoptionally one or more pair of substituents together with the atoms towhich they are bonded form a 3 to 7 member ring.

The term “alkanoyl” refers to alkyl group (which may be optionallysubstituted as described above) linked to a carbonyl group (i.e.—C(O)-alkyl). Similarly, the term “aroyl” refers to an aryl group (whichmay be optionally substituted as described above) linked to a carbonylgroup (i.e., —C(O)-aryl).

Throughout the specification, groups and substituents thereof may bechosen to provide stable moieties and compounds.

The compounds of formula I form salts which are also within the scope ofthis invention. Reference to a compound of the formula I herein isunderstood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic and/orbasic salts formed with inorganic and/or organic acids and bases. Inaddition, when a compound of formula I contains both a basic moiety andan acidic moiety, zwitterions (“inner salts”) may be formed and areincluded within the term “salt(s)” as used herein. Pharmaceuticallyacceptable (i.e., non-toxic, physiologically acceptable) salts arepreferred, although other salts are also useful, e.g., in isolation orpurification steps which may be employed during preparation. Salts ofthe compounds of the formula I may be formed, for example, by reacting acompound I with an amount of acid or base, such as an equivalent amount,in a medium such as one in which the salt precipitates or in an aqueousmedium followed by lyophilization.

The compounds of formula I which contain a basic moiety may form saltswith a variety of organic and inorganic acids. Exemplary acid additionsalts include acetates (such as those formed with acetic acid ortrihaloacetic acid, for example, trifluoroacetic acid), adipates,alginates, ascorbates, aspartates, benzoates, benzenesulfonates,bisulfates, borates, butyrates, citrates, camphorates,camphorsulfonates, cyclopentanepropionates, digluconates,dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates,glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides(formed with hydrochloric acid), hydrobromides (formed with hydrogenbromide), hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates(formed with maleic acid), methanesulfonates (formed withmethanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates,oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates,picrates, pivalates, propionates, salicylates, succinates, sulfates(such as those formed with sulfuric acid), sulfonates (such as thosementioned herein), tartrates, thiocyanates, toluenesulfonates such astosylates, undecanoates, and the like.

The compounds of formula I which contain an acidic moiety may form saltswith a variety of organic and inorganic bases. Exemplary basic saltsinclude ammonium salts, alkali metal salts such as sodium, lithium, andpotassium salts, alkaline earth metal salts such as calcium andmagnesium salts, salts with organic bases (for example, organic amines)such as benzathines, dicyclohexylamines, hydrabamines (formed withN,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines,N-methyl-D-glucamides, t-butyl amines, and salts with amino acids suchas arginine, lysine and the like.

Basic nitrogen-containing groups may be quaternized with agents such aslower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides,bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl,dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl,myristyl and stearyl chlorides, bromides and iodides), aralkyl halides(e.g. benzyl and phenethyl bromides), and others.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. The term “prodrug”, as employed herein, denotes acompound which, upon administration to a subject, undergoes chemicalconversion by metabolic or chemical processes to yield a compound of theformula I, or a salt and/or solvate thereof. Solvates of the compoundsof formula I are preferably hydrates.

To the extent that compounds of the formula I, and salts thereof, mayexist in their tautomeric form, all such tautomeric forms arecontemplated herein as part of the present invention.

All stereoisomers of the present compounds, such as those which mayexist due to asymmetric carbons on the various R and Z substituents,including enantiomeric forms (which may exist even in the absence ofasymmetric carbons) and diastereomeric forms, are contemplated withinthe scope of this invention. Individual stereoisomers of the compoundsof the invention may, for example, be substantially free of otherisomers, or may be admixed, for example, as racemates or with all other,or other selected, stereoisomers. The chiral centers of the presentinvention can have the S or R configuration as defined by the IUPAC 1974Recommendations.

The terms “including”, “such as”, “for example” and the like areintended to refer to exemplary embodiments and not to limit the scope ofthe present invention.

Schemes

Compounds of formula I may be prepared using the sequence of stepsoutlined below.

Compounds 1, 2 and 4 used in this preparation are commercially availableor are readily prepared by methods well known to those skilled in theart. For example compounds of formula 1 where R³=CONZ⁵Z⁶ can be preparedby the method of Witzeman (JOC 1991, 56(5), 1713) which involves warmingan amine and a t-butoxy-β-ketoester neat or in a suitable solvent(xylenes, toluene, etc.)

Alternately compounds of formula 1 where R⁴=methyl and R³=CONZ⁵Z⁶ may beprepared by reaction of an amine with diketene in a suitable solventsuch as dichloromethane at temperatures between −100-22° C.

Compounds of formula 3 can be prepared by modification of the Knovenagelcondensation. For example condensation of a compound of formula 1 and acompound of formula 2 at temperatures between 22-170° C. in solventssuch as toluene or dimethylformamide in the presence of an acid such asacetic acid and an a base such as piperidine with removal of watergenerated during the reaction by the use of 4 Å dry molecular sieves ora Dean-Stark trap affords compounds of formula 3 as a mixture of cis andtrans stereoisomers.

Compounds of formula I may also be prepared by condensation of compoundsof formula 3 with compounds of formula 4 by warming at temperaturesbetween 30-150° C. in alcoholic solvents such as ethanol or propanol orby warming between 30-150° C. in a solvent such as dimethylformamide andin the presence of a base such as sodium acetate.

Compounds of formula I where R³=ester may be prepared by condensation ofcompounds of formula 1, formula 2 and heterocycles of formula 4 bywarming between temperatures of 30-150° C. in the presence of a basesuch as sodium carbonate or sodium bicarbonate in a suitable solventsuch as dimethylformamide.

Compounds of formula I where R³=amide maybe prepared by treatingcompounds of formula I where R³=ester with a suitable amine andtrimethylaluminium in a solvent such as toluene at temperatures between0-150° C.

Compounds of formula I where R³=amide may also be prepared by condensingcompounds of formula I where R³=COOH with a suitable amine by amidationmethods well known to those skilled in the art. For example treatment ofa compound of formula I where R³=COOH with1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI) anddimethylaminopyridine (DMAP) in a solvent such as dichloromethaneaffords compounds of formula I where R³=amide.

Compounds of formula I where R⁵ is a substituent other than hydrogen maybe formed by reacting a compound of formula 5 with a reactive speciesM-R⁵ such that a compound of formula Ia is obtained, where M is Cl, Br,OR etc., and R⁵ is as defined above (other than hydrogen).

Compounds of formula I where X¹, X² and X³ form a ring of the structure

where R⁶ is a substituent other than hydrogen may be formed by reactinga compound of formula 7 with a reactive species M-R⁶ such that acompound of formula Ib is obtained where M is Cl, Br, OR, etc. and R⁶ isas defined above.

Compounds of formula Ic where R³ is a amino containing heterocycle maybe formed by condensing compounds of formula I where R³ is an acid orester with an amine which is attached through a linker to M. M may beNH₂, NHR, SH, or OH. The linker unit may be selected such thatunsubstituted, substituted or fused heterocycles are formed.

Additional compounds within the scope of the present invention can beprepared from the compounds obtained by the above described methodsthrough conversion of the substituent groups to other functionality bythe usual methods of chemical synthesis, as illustrated in the followingexamples.

Compounds of formula I that contain chiral centers maybe obtained innon-racemic form by non-racemic synthesis or resolution by methods wellknown to those skilled in the art. Compounds that are non-racemic aredesignated as “chiral” in the examples.

In the examples described below it may be necessary to protect reactivefunctionality such as hydroxy, amino, thio or carboxy groups, wherethese are desired in the final product, to avoid their unwantedparticipation in reactions. The introduction and removal of protectinggroups are well known to those skilled in the art, for example see(Green, T. W. in “Protective Groups in Organic Synthesis”, John Wileyand Sons, 1991).

Utility

Compounds within the scope of the present invention inhibit the K_(v)1subfamily of voltage-gated K⁺ channels, and as such are useful in thetreatment and/or prevention of various disorders: cardiac arrhythmias,including supraventricular arrhythmias, atrial arrhythmias, atrialflutter, atrial fibrillation, complications of cardiac ischemia, and useas heart rate control agents; angina pectoris including relief ofPrinzmetal's symptoms, vasospastic symptoms and variant symptoms;gastrointestinal disorders including reflux esauphagitis, functionaldispepsia, motility disorders (including constipation and diarrhea), andirritable bowel syndrome; disorders of vascular and visceral smoothmuscle including asthma, chronic obstructive pulmonary disease, adultrespiratory distress syndrome, peripheral vascular disease (includingintermittent claudication), venous insufficiency, impotence, cerebraland coronary spasm and Raynaud's disease; inflammatory and immunologicaldisease including inflammatory bowel disease, rheumatoid arthritis,graft rejection, asthma. chronic obstructive pulmonary disease, cysticfibrosis and atherosclerosis; cell poliferative disorders includingrestenosis and cancer (including leukemia); disorders of the auditorysystem; disorders of the visual system including macular degenerationand cataracts; diabetes including diabetic retinopathy, diabeticnephropathy and diabetic neuropathy; muscle disease including myotoniaand wasting; peripheral neuropathy; cognitive disorders; migraine;memory loss including Alzheimer's and dementia; CNS mediated motordysfunction including Parkinson's disease, and ataxia; epilepsy; andother ion channel mediated disorders.

As inhibitors of the K_(v)1 subfamily of voltage-gated K⁺ channelscompounds of the present invention are useful to treat a variety ofdisorders including resistance by transplantation of organs or tissue,graft-versus-host diseases brought about by medulla ossiumtransplantation, rheumatoid arthritis, systemic lupus erythematosus,hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type Idiabetes uveitis, juvenile-onset or recent-onset diabetes mellitus,posterior uveitis, allergic encephalomyelitis, glomerulonephritis,infectious diseases caused by pathogenicmicroorganisms, inflammatory andhyperproliferative skin diseases, psoriasis, atopical dermatitis,contact dermatitis, eczematous dermatitises, seborrhoeis dermatitis,Lichen planus, Pemphigus, bullous pemphigoid, Epidermolysis bullosa,urticaria, angioedemas, vasculitides, erythemas, cutaneouseosinophilias, Lupus erythematosus, acne, Alopecia areata,keratoconjunctivitis, vernal conjunctivitis, uveitis associated withBehcet's disease, keratitis, herpetic keratitis, conical cornea,dystrophia epithelialis corneae, corneal leukoma, ocular pemphigus,Mooren's ulcer Scleritis, Graves' opthalmopathy, Vogt-Koyanagi-Haradasyndrome, sarcoidosis, pollen allergies, reversible obstructive airwaydisease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsicasthma, dust asthma, chronic or inveterate asthma, late asthma andairway hyper-responsiveness, bronchitis, gastric ulcers, vascular damagecaused by ischemic diseases and thrombosis, ischemic bowel diseases,inflammatory bowel diseases, necrotizing enterocolitis, intestinallesions associated with thermal burns and leukotriene B₄-mediateddiseases, Coeliaz diseases, proctitis, eosinophilic gastroenteritis,mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis,eczema, interstitial nephritis, Good-pasture's syndrome,hemolytic-uremic syndrome, diabetic nephropathy, multiple myositis,Guillain-Barre syndrome, Meniere's disease, polyneuritis, multipleneuritis, mononeuritis, radiculopathy, hyperthroidism, Basedow'sdisease, pure red cell aplasia, aplastic anemia, hypoplastic anemia,idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia,agranulocytosis, pernicious anemia, megaloblastic anemia,anerythroplasia, osteoporosis, sarcoidosis, fibroid lung, idopathicinterstitial pneumonia, dermatomyositis, leukoderma vulgaris, ichthyosisvulgaris, photoallergic sensitivity, cutaneous T cell lymphoma,arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritisnodosa, myocardosis, scleroderma, Wegener's granuloma, Sjogren'ssyndrome, adiposis, eosinophilic fascitis, lesions of gingiva,periodontium, alveolar bone, substantia osses dentis,glomerulonephritis, male pattern alopecia or alopecia senilis bypreventing epilation or providing hair germination and/or promoting hairgeneration and hair growth, muscular dystrophy; Pyoderma and Sezary'ssyndrome, Addison's disease, ischemia-reperfusion injury of organs whichoccurs upon preservation, transplantation or ischemic disease,endotoxin-shock, pseudomembranous colitis, colitis caused by drug orradiation, ischemic acute renal insufficiency, chronic renalinsufficiency, toxinosis caused by lung-oxygen or drugs, lung cancer,pulmonary emphysema, cataracta, siderosis, retinitis, pigentosa, senilemacular degeneration, vitreal scarring, corneal alkali burn, dermatitiserythema multiforme, linear IgA ballous dermatitis and cementdermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseasescaused by environmental pollution, aging, carcinogenis, metastatis ofcarcinoma and hypobaropathy, disease caused by histamine orleukotriene-C₄ release, Behcet's disease, autoimmune hepatitis, primarybiliary cirrhosis sclerosing cholangitis, partial liver resection, acuteliver necrosis, necrosis caused by toxin, viral hepatitis, shock, oranoxia, B-virus hepatitis, non-A/non-B hepatitis, cirrhosis, alcoholiccirrhosis, hepatic failure, fulminant hepatic failure, late-onsethepatic failure, “acute-on-chronic” liver failure, augention ofchemotherapeutic effect, cytomegalovirus infection, HCMV infection,AIDS, cancer, senile dementia, trauma, and chronic bacterial infection.

The compounds of the present invention are antiarrhythmic agents whichare useful in the prevention and treatment (including partialalleviation or cure) of arrhythmias. As inhibitors of K_(v)1.5 compoundswithin the scope of the present invention are particularly useful in theselective prevention and treatment of supraventricular arrhythmias suchas atrial fibrillation, and atrial flutter. By “selective prevention andtreatment of supraventricular arrhythmias” is meant the prevention ortreatment of supraventricular arrhythmias wherein the ratio of theprolongation of the atrial effective refractory period to theprolongation of the ventricular effective refractory period is greaterthan 1:1. This ratio is preferably greater than 4:1, more preferablygreater than 10:1, and most preferably such that prolongation of theatrial effective refractory response period is achieved withoutsignificantly detectable prolongation of the ventricular effectiverefractory period.

In addition, the compounds within the scope of the present inventionblock I_(Kur), and thus may be useful in the prevention and treatment ofall I_(Kur)-associated conditions. An “I_(Kur)-associated condition” isa disorder which may be prevented, partially alleviated or cured by theadministration of an I_(Kur) blocker. The Kv1.5 gene is known to beexpressed in stomach tissue, intestinal/colon tissue, the pulmonaryartery, and pancreatic beta cells. Thus, administration of an I_(Kur)blocker could provide useful treatment for disorders such as: refluxesauphagitis, functional dispepsia, constipation, asthma, and diabetes.Additionally, Kv1.5 is known to be expressed in the anterior pituitary.Thus, administration of an I_(Kur) blocker could stimulate growthhormone secretion. I_(Kur) inhibitors can additionally be useful in cellpoliferative disorders such as leukemia, and autoimmune diseases such asrheumatoid arthritis and transplant rejection.

The present invention thus provides methods for the prevention ortreatment of one or more of the aforementioned disorders, comprising thestep of administering to a subject in need thereof an effective amountof at least one compound of the formula I. Other therapeutic agents suchas those described below may be employed with the inventive compounds inthe present methods. In the methods of the present invention, such othertherapeutic agent(s) may be administered prior to, simultaneously withor following the administration of the compound(s) of the presentinvention.

The present invention also provides pharmaceutical compositionscomprising at least one of the compounds of the formula I or saltsthereof capable of preventing or treating one or more of theaforementioned disorders in an amount effective therefor, and apharmaceutically acceptable vehicle or diluent. The compositions of thepresent invention may contain other therapeutic agents as describedbelow, and may be formulated, for example, by employing conventionalsolid or liquid vehicles or diluents, as well as pharmaceuticaladditives of a type appropriate to the mode of desired administration(for example, excipients, binders, preservatives, stabilizers, flavors,etc.) according to techniques such as those well known in the art ofpharmaceutical formulation.

The compounds of the formula I may be administered by any suitablemeans, for example, orally, such as in the form of tablets, capsules,granules or powders; sublingually; bucally; parenterally, such as bysubcutaneous, intravenous, intramuscular, or intrasternal injection orinfusion techniques (e.g., as sterile injectable aqueous or non-aqueoussolutions or suspensions); nasally such as by inhalation spray;topically, such as in the form of a cream or ointment; or rectally suchas in the form of suppositories; in dosage unit formulations containingnon-toxic, pharmaceutically acceptable vehicles or diluents. The presentcompounds may, for example, be administered in a form suitable forimmediate release or extended release. Immediate release or extendedrelease may be achieved by the use of suitable pharmaceuticalcompositions comprising the present compounds, or, particularly in thecase of extended release, by the use of devices such as subcutaneousimplants or osmotic pumps. In the case where the compounds of formula Iare being administered to prevent or treat arrhythmias, the compoundsmay be administered to achieve chemical conversion to normal sinusrhythm, or may optionally be used in conjunction with electricalcardioconversion.

Exemplary compositions for oral administration include suspensions whichmay contain, for example, microcrystalline cellulose for imparting bulk,alginic acid or sodium alginate as a suspending agent, methylcelluloseas a viscosity enhancer, and sweeteners or flavoring agents such asthose known in the art; and immediate release tablets which may contain,for example, microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and/or lactose and/or other excipients, binders,extenders, disintegrants, diluents and lubricants such as those known inthe art. The compounds of formula I may also be delivered through theoral cavity by sublingual and/or buccal administration. Molded tablets,compressed tablets or freeze-dried tablets are exemplary forms which maybe used. Exemplary compositions include those formulating the presentcompound(s) with fast dissolving diluents such as mannitol, lactose,sucrose and/or cyclodextrins. Also included in such formulations may behigh molecular weight excipients such as celluloses (avicel) orpolyethylene glycols (PEG). Such formulations may also include anexcipient to aid mucosal adhesion such as hydroxy propyl cellulose(HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methylcellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), and agentsto control release such as polyacrylic copolymer (e.g., Carbopol 934).Lubricants, glidants, flavors, coloring agents and stabilizers may alsobe added for ease of fabrication and use.

Exemplary compositions for nasal aerosol or inhalation administrationinclude solutions in saline which may contain, for example, benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, and/or other solubilizing or dispersing agents such asthose known in the art.

Exemplary compositions for parenteral administration include injectablesolutions or suspensions which may contain, for example, suitablenon-toxic, parenterally acceptable diluents or solvents, such asmannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodiumchloride solution, or other suitable dispersing or wetting andsuspending agents, including synthetic mono- or diglycerides, and fattyacids, including oleic acid.

Exemplary compositions for rectal administration include suppositorieswhich may contain, for example, a suitable non-irritating excipient,such as cocoa butter, synthetic glyceride esters or polyethyleneglycols, which are solid at ordinary temperatures, but liquify and/ordissolve in the rectal cavity to release the drug.

Exemplary compositions for topical administration include a topicalcarrier such as Plastibase (mineral oil gelled with polyethylene).

The effective amount of a compound of the present invention may bedetermined by one of ordinary skill in the art, and includes exemplarydosage amounts for an adult human of from about 0.001 to 100 mg/kg ofbody weight of active compound per day, which may be administered in asingle dose or in the form of individual divided doses, such as from 1to 4 times per day. It will be understood that the specific dose leveland frequency of dosage for any particular subject may be varied andwill depend upon a variety of factors including the activity of thespecific compound employed, the metabolic stability and length of actionof that compound, the species, age, body weight, general health, sex anddiet of the subject, the mode and time of administration, rate ofexcretion, drug combination, and severity of the particular condition.Preferred subjects for treatment include animals, most preferablymammalian species such as humans, and domestic animals such as dogs,cats and the like, subject to the aforementioned disorders.

The compounds of the present invention may be employed alone or incombination with each other and/or other suitable therapeutic agentsuseful in the treatment of the aforementioned disorders or otherdisorders, including: other antiarrhythmic agents such as Class I agents(e.g., propafenone), Class II agents (e.g., carvadiol and propranolol),Class III agents (e.g., sotalol, dofetilide, amiodarone, azimilide andibutilide), Class IV agents (e.g., diltiazem and verapamil), 5HTantagonists (e.g., sulamserod, serraline and tropsetron), anddronedarone; calcium channel blockers (both L-type and T-type) such asdiltiazem, verapamil, nifedipine, amlodipine and mybefradil;Cyclooxygenase inibitors (i.e., COX-1 and/or COX-2 inhibitors) such asaspirin, indomethacin, ibuprofen, piroxicam, naproxen, celebrex, vioxxand NSAIDs; anti-platelet agents such as GPIIb/IIIa blockers (e.g.,abciximab, eptifibatide and tirofiban), P2Y12 antagonists (e.g.,clopidogrel, ticlopidine and CS-747), thromboxane receptor antagonists(e.g., ifetroban), aspirin, and PDE-III inhibitors (e.g., dipyridamole)with or without aspirin; diruetics such as chlorothiazide,hydrochlorothiazide, flumethiazide, hydroflumethiazide,bendroflumethiazide, methylchlorothiazide, trichloromethiazide,polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone,furosemide, musolimine, bumetanide, triamtrenene, amiloride, andspironolactone; anti-hypertensive agents such as alpha adrenergicblockers, beta adrenergic blockers, calcium channel blockers, diuretics,renin inhibitors, ACE inhibitors, (e.g., captropril, zofenopril,fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril,quinapril, ramipril, lisinopril), A II antagonists (e.g., losartan,irbesartan, valsartan), ET antagonists (e.g. sitaxsentan, atrsentan andcompounds disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265), DualET/AII antagonist (e.g., compounds disclosed in WO 00/01389), neutralendopeptidase (NEP) inhibitors, vasopepsidase inhibitors (dual NEP-ACEinhibitors) (e.g., omapatrilat and gemopatrilat), nitrates, andcombinations of such anti-hypertensive agents;antithrombotic/thrombolytic agents such as tissue plasminogen activator(tPA), recombinant tPA, tenecteplase (TNK), lanoteplase (nPA), factorVIIa inhibitors, factor Xa inhibitors, thromin inibitors (e.g., hirudinand argatroban), PAI-1 inhibitors (i.e., inactivators of tissueplasminogen activator inhibitors), □2-antiplasmin inhibitors,streptokinase, urokinase, prourokinase, anisoylated plasminogenstreptokinase activator complex, and animal or salivary glandplasminogen activators; anticoagulants such as warfarin and heparins(including unfractionated and low molecular weight heparins such asenoxaparin and dalteparin); HMG-CoA reductase inhibitors such aspravastatin lovastatin, atorvastatin, simvastatin, NK-104 (a.k.a.itavastatin, or nisvastatin or nisbastatin) and ZD-4522 (a.k.a.rosuvastatin, or atavastatin or visastatin); other cholesterol/lipidlowering agents such as squalene synthetase inhibitors, fibrates, andbile acid sequestrants (e.g., questran); antipoliferative agents such ascyclosporin A, taxol, FK 506, and adriamycin; antitumor agents such astaxol, adriamycin, epothilones, cisplatin and carboplatin; anti-diabeticagents such as biguanides (e.g. metformin), glucosidase inhibitors (e.g.acarbose), insulins, meglitinides (e.g. repaglinide), sulfonylureas(e.g. glimepiride, glyburide and glipizide), biguanide/glyburidecombinations (i.e,. glucovance), thiozolidinediones (e.g. troglitazone,rosiglitazone and pioglitazone), PPAR-gamma agonists, aP2 inhibitors,and DP4 inhibitors; thyroid mimetics (including thyroid receptorantagonists) (e.g., thyrotropin, polythyroid, KB-130015, anddronedarone); Mineralocorticoid receptor antagonists such asspironolactone and eplerinone; growth hormone secretagogues;anti-osteoporosis agents (e.g., alendronate and raloxifene); hormonereplacement therapy agents such as estrogen (including conjugatedestrogens in premarin), and estradiol; antidepressants such asnefazodone and sertraline; antianxiety agents such as diazepam,lorazepam, buspirone, and hydroxyzine pamoate; oral contraceptives;anti-ulcer and gastroesophageal reflux disease agents such asfamotidine, ranitidine, and omeprazole; anti-obesity agents such asorlistat; cardiac glycosides including digitalis and ouabain;phosphodiesterase inibitors including PDE III inhibitors (e.g.cilostazol), and PDE V inhibitors (e.g., sildenafil); protein tyrosinekinase inhibitors; steroidal anti-inflammatory agents such asprednisone, and dexamethasone; and other anti-inflammatory agents suchas enbrel.

The above other therapeutic agents, when employed in combination withthe compounds of the present invention, may be used, for example, inthose amounts indicated in the Physicians' Desk Reference (PDR) or asotherwise determined by one of ordinary skill in the art.

Assays to determine the degree of activity of a compound as anI_(Kur)inhibitor are well known in the art and are described inreferences such as J. Gen. Physiol. April;101(4):513-43, and Br. J.Pharmacol. 1995 May;115(2):267-74.

Assays to determine the degree of activity of a compound as an inhibitorof other members of the K_(v)1 subfamily are also well known in the art.For example, inhibition of Kv1.1, K_(v)1.2 and K_(v) 1.3 can be measuredusing procedures described by

Grissmer S, et al., Mol Pharmacol 1994 June;45(6):1227-34. Inhibition ofKv1.4 can be measured using procedures described by Petersen K R, andNerbonne J M, Pflugers Arch 1999 February;437(3):381-92. Inhibition ofKv1.6 can be measured using procedures described by Bowlby M R, andLevitan I B, J Neurophysiol 1995 June;73(6):2221-9. And inhibition ofKv1.7 can be measured using procedures described by Kalman K, et al., J.Biol Chem 1998 March 6;273(10):5851-7.

Compounds within the scope of the present invention demonstrate activityin K_(v)1 assays such as the ones described above.

All documents cited in the present specification are incorporated hereinby reference in their entirety.

The following examples and preparations describe the manner and processof making and using the invention and are illustrative rather thanlimiting. It is to be understood that there may be other embodimentswhich fall within the spirit and scope of the invention as defined bythe claims appended hereto. Abbreviations employed herein are definedbelow.

-   CDI=carbonyl diimidazole-   DCM=dichloromethane-   DMAP=dimethylaminopyridine-   DMF=dimethylformamide-   DMPU=1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone-   EDCI (or EDC)=1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide    hydrochloride-   M+H=monoisotopic mass plus one proton-   Et=ethyl-   h=hours-   HPLC=high performance liquid chromatography-   HOBT=hydroxybenzotriazole-   LC/MS=liquid chromatography/mass spectrometry-   Me=methyl-   min=minutes-   MS=mass spectrometry-   NaOAc=sodium acetate-   Ph=phenyl-   PPA=poly phosphoric acid-   Pr=propyl-   Py=pyridine-   PyBrOP=bromo-tris-pyrrolidino-phosphonium hexafluorophosphate-   RT=room temperature-   Rt=retention time-   TEA=triethylamine-   TFA=trifluoroacetic acid-   TLC=thin layer chromatography-   THF=tetrahydrofuran-   TMSOTf=trimethylsilyl trifluoromethanesulfonate

EXAMPLE 17-(2,3-Dichlorophenyl)-4,7-dihydro-5-methylpyrazolo[1,5-a]pyrimidine-6-carboxylicacid methyl ester

Method:

Step A: A mixture of methyl acetoacetate 1 (5 mL, 46 mmol),2,3-dichlorobenzaldehyde 2 (8.1 g, 46 mmol), piperidine (1.1 ml, 12mmol), and acetic acid (0.6 mL, 11 mmol) in toluene (200 mL) wasrefluxed overnight with azeotropic removal of water via a Dean-Starktrap. The mixture was cooled to room temperature, quenched with water,transferred to a separatory funnel, diluted with ethyl acetate, washedwith aqueous NaOH (1M), aqueous HCl (1M), water and brine andconcentrated in vacuo. The residue was purified by flash chromatography(silica gel, 33% Ethyl acetate/hexanes) to afford 10.8 g (85% yield) ofcompound 3 as a mixture of diasteromers. Reverse Phase LC/MS: YMC S5 ODS4.6×50 mm Ballistic column, UV detection at 220λ, 4 min. gradient (10%MeOH/H₂O with 0.1% TFA-90% MeOH/H₂O with 0.1% TFA), 4 mL/min.Diastereomer A, Rt=3.51 min, (53%) Diastereomer B, Rt=3.70 min (45%). MS(M+H: 273).

Step B: A mixture of compound 3 (5 g, 18.3 mmol), 3-aminopyrazole 4 (1.5g, 18.3 mmol) in 1-propanol (60 mL) was refluxed for 6 h. The mixturewas cooled to room temperature and concentrated and recrystallized fromethyl acetate/hexanes to give 1.25 g (20%) of the title compound as ayellow solid. The mother liquor was concentrated and purified by flashchromatography (silica gel, 5% methanol/dichloromethane) to give anadditional 1.62 g (26%) of the title compound. Combined yield 2.87 g(46%). Reverse Phase LC/MS: YMC S5 ODS 4.6×50 mm Ballistic column, UVdetection at 220λ, 4 min. gradient (10% MeOH/H₂O with 0.1% TFA-90%MeOH/H₂O with 0.1% TFA), 4 mL/min. Rt=3.38 min, (96% pure). MS (M+H:338). HMR (CDCl₃, 400 MHz) 7.98(1H, app. s), 7.15(3H, m), 6.91(1H, s),5.52(1H, app. s), 3.61(3H, s), 2.39(3H, s).

EXAMPLES 2 AND 3

The compounds of Examples 2 and 3, shown in the table provided below,were prepared in a manner similar to that described in Example 1. Ex-am- (M + ple Structure Name H) 2

7-(3,4-Dichlorophenyl)- 4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidine-6- carboxylic acid methyl ester 338 3

7-(4-Chlorophenyl)-4,7- dihydro-5- methylpyrazolo[1,5- a]pyrimidine-6-carboxylic acid methyl ester 303

EXAMPLE 47-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazolo[1,5-a]pyrimidine-6-carboxylicacid 1,1-dimethylethyl ester

Method 1:

Compound 1: Compound 1 was prepared by condensing t-butoxyacetoacetateand 2,4-dichlorobenzaldehyde as described in Example 1 step A.

Title Compound: A mixture of compound 1 (44.4 g, 141 mmol),3-aminopyrazole 2 (17.6 g 212 mmol) and sodium acetate (46.3 g, 564mmol) in dimethylformamide (300 mL) was stirred at 70° C. overnight (17h). The mixture was cooled to room temperature, transferred to aseparatory funnel, diluted with water and ethyl acetate, washed withwater (a small amount of methanol was added to breakup emulsions thatformed) and brine, dried over anhydrous sodium sulfate and concentrated.A precipitate formed. The precipitate was collected and washed withethyl acetate, ethyl ether and hexanes and dried to give 8.93 g. Themother liquor was concentrated to give a second crop of precipitate 9.32g. LC/MS analysis indicated the precipitates were not pure. Theprecipitates were combined, dissolved in dichloromethane andconcentrated onto enough silica gel such that a free flowing powder wasobtained. The resulting powder was loaded onto a chromatography columnprepacked with silica gel and dichloromethane. Elution with 100%dichloromethane followed by 3% methanol/dichloromethane gave 15.1 g (29%yield) of the title compound. Reverse Phase LC/MS: YMC S5 ODS 4.6×50 mmBallistic column, UV detection at 220λ, 4 min. gradient (10% MeOH/H20with 0.1% TFA-90% MeOH/H₂O with 0.1% TFA), 4 mL/min. Rt=4.63 min, (97%pure). MS (M+H: 380). HMR (CD₃OD, 400 MHz) 7.41(2H, m), 7.33(1H, d, J=2Hz), 7.08(1H, m), 6.21(1H, s), 5.68(1H, d, J=2 Hz), 2.43(3H, s),1.37(9H, s).

Method 2:

A mixture of t-butoxyacetoacetate 1 (22.6 g, 143 mmol),3,4-dichlorobenzaldehyde 2 (25.0 g, 143 mmol), 3-aminopyrazole 3 (15.4g, 185 mmol) and sodium bicarbonate (36 g, 428 mmol) indimethylformamide (250 mL) was stirred at 70° C. overnight (18 h). Themixture was cooled to room temperature, quenched with ethyl acetate andwater, transferred to a separatory funnel, washed with water and brine,dried over sodium sulfate, filtered and concentrated. The residue wasrecrystallized from ethyl acetate/hexanes to give 16.8 g (31% yield) ofthe title compound as a white solid. Data for the title compound isgiven in method 1.

EXAMPLES 5 AND 6

The compounds of Examples 5 and 6, shown in the table provided below,were prepared in a manner similar to that described in Example 4,Method 1. Example Structure Name (M + H) 5

7-(3,4-Dichlorophenyl)- 4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazolo [1,5-a]pyrimidine-6- carboxylic acid 1,1-dimethylethyl ester 448 6

7-(2,3-Dichlorophenyl)- 4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazolo [1,5-a]pyrimidine-6- carboxylic acid 1,1-dimethylethyl ester 448

EXAMPLES 7-11

The compounds of Examples 7-11, shown in the table provided below, wereprepared in a manner similar to that described in Example 4, Method 2.The compound of Example 4, method 2 could be resolved into thecorresponding enantiomers A (Example 8) and B (Example 9) by preparativechiral HPLC (Chiralcel OD column (50×500 mm), eluting with 7%isopropanol/hexanes containing 0.1% triethylamine amine at 50 mL/min),UV detection at 254λ. Analytical HPLC (Chiralcel OD column (4.6×250 mm)eluting with 10% isopropanol/hexanes containing 0.1% triethylamine amineat 1 mL/min), UV detection at 254λ, enantiomer A (Rt=6.98 min, 98% ee)enantiomer B (Rt=9.22 min, 98% ee). Example Structure Name (M + H) 7

7-(2,3-Dichlorophenyl)- 4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid 1,1-dimethylethyl ester 380 8

7-(3,4-Dichlorophenyl)- 4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid 1,1-dimethylethylester, enantiomer A 3809

7-(3,4-Dichlorophenyl)- 4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid 1,1-dimethylethylester, enantiomer B 38010 

7-(3,4-Dichlorophenyl)- 4,7-dihydro-2,5- dimethylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid 1,1-dimethylethyl ester 394 11 

3-Chloro-7-(3- chlorophenyl)-4,7-dihydro- 5-methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid 1,1-dimethylethyl ester 380

EXAMPLE 127-(2,3-Dichlorophenyl)-4,7-dihydro-4,5-dimethylpyrazolo[1,5-a]pyrimidine-6-carboxylicacid 1,1-dimethylethyl ester

Method:

Compound 1: Compound 1 was prepared as described in Example 4, method 1.

Title Compound: Sodium hydride (0.186 g, 7.76 mmol) was added to a 0° C.solution of 1 (2.27 g, 5.97 mmol) in dimethylformamide (30 mL). After 10min., methyl iodide (0.41 mL, 6.57 mmol) was added. After an additional85 min, the mixture was quenched with saturated ammonium chloridesolution, diluted with ethyl acetate, transferred to a separatoryfunnel, washed with saturated ammonium chloride, water and brine, driedover anhydrous sodium sulfate and concentrated onto enough silica gelsuch that a free flowing powder was obtained. The resulting powder wasloaded onto a chromatography column prepacked with 100% dichloromethane.Elution with 0-10% ethyl acetate/dichloromethane gave 1.16 g (49%) ofthe tile compound as a slightly yellow solid. Reverse Phase LC/MS: YMCS5 ODS 4.6×50 mm Ballistic column, UV detection at 220λ, 4 min. gradient40-100% Solvent B/A (Solvent A: 10% MeOH/H20 with 0.1% TFA, Solvent B:90% MeOH/H₂O with 0.1% TFA), 4 mL/min. Rt=3.46 min, (96% pure). MS (M+H:394). HMR (CD₃Cl, 400 MHz) 7.39(1H, d, J=2 Hz), 7.35(1H, m), 7.23(1H,m), 7.11(1H, m), 6.91(1H, s), 5.58(1H, d, J=2 Hz), 2.38(3H, s), 2.62(3H,s), 1.27(9H, s).

EXAMPLE 137-(3,4-Dichlorophenyl)-4,7-dihydro-4,5-dimethylpyrazolo[1,5-a]pyrimidine-6-carboxylicacid 1,1-dimethylethyl ester

The title compound was prepared in a similar manner to that provided inExample 12 yielding a compound with (M+H): 394.

EXAMPLE 144,7-Dihydro-5-methyl-7-(1-methylethyl)pyrazolo[1,5-a]pyrimidine-6-carboxylicacid 1,1-dimethylethyl ester

Method:

A pressure tube was dried with a heat gun under nitrogen. The pressuretube was charged in the following order with isobutyraldehyde 2 (0.262g, 3.63 mmol), dimethylformamide (3 mL), t-butylacetoacetate 1 (0.574 g,3.63 mmol), 3-aminopyrazole 3 (0.362 g, 4.36 mmol) and sodium acetate(1.22 g, 14.5 mmol). The mixture was flushed with nitrogen. The tube wassealed and warmed to 75° C. and stirred overnight. The mixture wascooled to room temperature, diluted with ethyl acetate to a volume of 20mL, washed with lithium chloride (2.4M, 10 mL) and brine, dried overanhydrous sodium sulfate, filtered and concentrated to give 1.02 of ayellow oil. The oil was purified by flash chromatography (silica, 45%ethyl acetate/heptane) to give 0.42 g (41% yield) of the title compound.Reverse Phase HPLC: YMC S5 ODS 4.6×50 mm Ballistic column, UV detectionat 220λ, 4 min. gradient 0-100% Solvent B/A (Solvent A: 10% MeOH/H₂Owith 0.2% PPA, Solvent B: 90% MeOH/H₂O with 0.2% PPA), 4 mL/min. Rt=3.83min, (100% pure). Reverse Phase LC/MS: YMC S5 ODS 4.6×50 mm Ballisticcolumn, UV detection at 220λ, 4 min. gradient 0-100% Solvent B/A(Solvent A: 10% MeOH/H₂O with 0.1% TFA, Solvent B: 90% MeOH/H₂O with0.1% TFA), 4 mL/min. Rt=3.06 min. MS (EM, M+1: 278). HMR (CDCl₃, 400MHz): 7.37(1H, d, J=2.2 Hz), 6.35(1H, s), 5.55(1H, d, J=1.8 Hz),5.29(1H, d, J=2.2 Hz), 2.41(3H, s), 1.50(9H, s), 1.28-1.19(1H, m),1.07(3H, d, J=7.0 Hz), 0.60(3H, d, J=7.0 Hz).

EXAMPLE 157-Cyclopropyl-4,7-dihydro-5-methylpyrazolo[1,5-a]pyrimidine-6-carboxylicacid 1,1-dimethylethyl ester

The title compound was prepared in a similar manner to that provided inExample 14 yielding a compound with (M+H): 275.

EXAMPLE 167-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazolo[1,5-a]pyrimidine-6-carboxylicacid

Method:

Compound 1: Compound 1 was prepared as described in Example 4.

Title Compound: HCl (4M in dioxane) was added to solid compound 1 (1.13g, 2.97 mmol) at room temperature. The solid dissolves and a precipitateforms. The resulting thick reaction mixture was allowed to stirovernight and was concentrated in vacuo to give 1.14 g (120% containsdioxane) of the title compound as a white solid. Reverse Phase LC/MS:YMC S5 ODS 4.6×50 mm Ballistic column, UV detection at 220λ, 4 min.gradient 0-100% Solvent B/A (Solvent A: 10% MeOH/H2O with 0.1% TFA,Solvent B: 90% MeOH/H₂O with 0.1% TFA), 4 mL/min. Rt=3.54 min, (93%pure). MS (M+H: 324). HMR (CD₃OD, 400 MHz) 7.96(1H, d, J=3 Hz), 7.51(2H,m), 7.21(1H, m), 6.49(1H, s), 6.11(1H, d, J=3 Hz), 2.51(3H, s). Thetitle compound was used in subsequent reactions without furtherpurification.

EXAMPLE 177-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-6-carboxylicacid

Method:

Compound 1: Compound 1 (the compound of Example 5) was prepared in amanner similar to that described in Example 4.

Title Compound: Trimethylsilyl trifluoromethanesulfonate (0.873 mL, 4.82mmol) was added to a room temperature solution of compound 1 (1.08 g,2.41 mmol) in dichloromethane (50 mL). After 2 h triethylamine (0.672ml, 4.82 mmol) was added and the reaction mixture was poured into water.The organic layer was separated and dried over Na₂SO₄, concentrated, andpurified by flash chromatography (50% ethylacetate/hexane→100% ethylacetate) to give 0.71 g (75% yield) of the title compound as a whitesolid. MS (M+H: 392).

EXAMPLE 181-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl]carbonyl]-4-phenylpiperazine

Method 1:

Compound 1: Compound 1 was prepared as described in Example 1.

Title Compound: Trimethylaluminium (1.1 mL, 2.2 mmol, 2 M in toluene)was dropwise added to a room temperature solution of 1-phenypiperazine 2(0.4 mL, 2.2 mmol) in toluene (7 mL). After one hour compound 1 (0.50 g,1.5 mmol) was added and the resulting mixture was stirred at 100° C. for18 h. The mixture was cooled to room temperature, quenched with water,diluted with ethyl acetate, transferred to a separatory funnel, washedwith aqueous HCl (1M), water and brine, dried over anhydrous sodiumsulfate and concentrated in vacuo. The residue was purified by flashchromatography (silica gel, 50% ethyl acetate/hexanes followed by 5%methanol/dichloromethane to provide 0.22 g (32%) of a solid which wasfurther purified by recrystallization from methanol/ethyl ether to give0.15 g (22%) of the title compound. Reverse Phase LC/MS: YMC S5 ODS4.6×50 mm Ballistic column, UV detection at 220λ, 4 min. gradient 0-100%Solvent B/A (Solvent A: 10% MeOH/H20 with 0.1% TFA, SolventB: 90%MeOH/H₂O with 0.1% TFA), 4 mL/min. Rt=3.58 min, (92% pure). MS (M+H:468). Additional Data for the title compound is reported in Method 2,step C variation 1.

Method 2:

Step A Variation 1: A mixture of N-phenylpiperazine 1 (6.7 mL, 41 mmol)and t-butoxyacetoacetate 2 (6.8 mL, 45 mmol) in toluene (50 mL) wasrefluxed overnight. The mixture was cooled to room temperature,transferred to a separatory funnel, diluted with ethyl ether andextracted (3×) with aqueous HCl (1M). The HCl extracts were combined andwashed with ethyl ether (2×), made basic (pH 9) with aqueous NaOH (50%w/w) and extracted with ethyl acetate. The ethyl acetate extracts werecombined, washed with water and brine, dried over anhydrous sodiumsulfate, filtered and concentrated to give 9.76 g (97.6%) of compound 4as a thick amber oil. Reverse Phase LC/MS: YMC S5 ODS 4.6×50 mmBallistic column, UV detection at 220λ, 4 min. gradient 0-100% SolventB/A (Solvent A: 10% MeOH/H20 with 0.1% TFA, SolventB: 90% MeOH/H₂O with0.1% TFA), 4 mL/min. Rt=1.65 min, (100% pure). MS (M+H: 247). HMR(CDCl₃, 400 MHz) 7.28(2H, m), 6.91(3H, m), 3.80(2H, m), 3.78(2H, m),3.59(4H, m), 3.19(4H, m), 2.30(3H, s).

Step A Variation 2: Diketene 3 (5.50 g, 65.5 mmol) was slowly added over15 min. to a 0° C. solution of 4-phenylpiperazine 1 (5.31 g, 32.7 mmol)in dichloromethane (50 mL). TLC after 4 h indicated compound 1 was notcompletely consumed. Additional diketene (5.50 g, 65.5 mmol) was added.After an additional 1.5 h the reaction was quenched with 1N NaOH,transferred to a separatory funnel, washed with 1H NaOH and brine, driedover sodium sulfate, concentrated onto enough silica gel such that afree flowing powder was obtained. The resulting powder was loaded onto achromatography column prepacked with silica and 50% ethylacetate/hexanes. Elution with 50-100% ethylacetate/hexanes gave 8.2 g(100%) of compound 4 as a thick yellow oil. Data for compound 4 is givenabove in step A variation 1.

Step B: A mixture of compound 4 (9.76 g, 40 mmol),2,3-dichlorobenzaldehyde 6 (7.89 g, 45 mmol), piperidine (1.0 ml, 10mmol), acetic acid (0.59 mL, 10 mmol) in toluene (100 mL) was refluxedovernight with azeotropic removal of water via a Dean-Stark trap. Themixture was cooled to room temperature and concentrated in vacuo and wastypically used in subsequent reactions without purification. Compound 6may be Purified by silica gel chromatography (30-40% ethylacetate/hexanes). Reverse Phase LC/MS: YMC S5 ODS 4.6×50 mm Ballisticcolumn, WV detection at 220λ, 4 min. gradient 0-100% Solvent B/A(Solvent A: 10% MeOH/H20 with 0.1% TFA, SolventB: 90% MeOH/H₂O with 0.1%TFA), 4 mL/min. Rt=3.83 min, (96% pure). MS (M+H: 404). HMR (CDCl₃, 400MHz) 7.82(1H, s), 7.55(1H, dd, J=1, 8 Hz), 7.48(1H, dd, J=1, 8 Hz),7.23(3H, m), 6.89(1H, app. t, 7 Hz), 6.81(2H, d, J=8 Hz), 3.78(2H, m),3.34(1H, m), 3.23(2H, m), 2.96(1H, m), 2.85(1H, m), 2.50(3H, s),2.42(1H, M).

Step C Variation 1: A mixture of compound 6 (16 g, 40 mmol),3-aminopyrazole 7 (5.1 g 62 mmol) and sodium acetate (10.1 g, 123 mmol)in dimethylformamide (100 mL) was stirred at 70° C. overnight (17 h).The mixture was cooled to room temperature, transferred to a separatoryfunnel, diluted with water and ethyl acetate, washed with water (a smallamount of methanol was added to breakup emulsions that formed) andbrine, dried over anhydrous sodium sulfate and concentrated. Theresulting residue was purified by silica gel chromatography. Elutionwith 50% ethyl acetate/hexanes followed by 100% ethyl acetate afforded6.2 g (33% yield from compound 1) of the title compound. The titlecompound could be resolved into the corresponding enantiomers A (Example28) and B (Example 29) by preparative chiral HPLC (Chiracel OD column(50×500 mm), eluting with 30% isopropanol/hexanes containing 0.1%triethylamine amine at 50 mL/min), UV detection at 254λ, enantiomer ARt=42 min, enantiomer B Rt=54 min. Analytical HPLC (Chiracel OD column(4.6×250 mm) eluting with 30% isopropanol/hexanes containing 0.1%triethylamine amine at 1 mL/min), UV detection at 254λ, enantiomer ARt=11.7 min, enantiomer B Rt=17.6 min. Data given for enantiomer A:Reverse Phase LC/MS: YMC S5 ODS 4.6×50 mm Ballistic column, UV detectionat 220λ, 4 min. gradient 0-100% Solvent B/A (Solvent A: 10% MeOH/H20with 0.1% TFA, Solvent B: 90% MeOH/H₂O with 0.1% TFA), 4 mL/min. Rt=3.54min, (91% pure). MS (M+H: 468). HMR (HCl salt of 8a, CD₃OD, 400 MHz)7.94(1H, d, J=3 Hz), 7.56(8H, m), 7.38(1H, m), 6.05(1H, d, J=3 Hz),4.23(1H, m), 3.57(7H, m), 2.01(3H, s).

Step C Variation 2: A mixture of compound 5 (6.0 g, 15 mmol),3-aminopyrazole 7 (1.24 g, 15 mmol) in n-propanol (50 mL) was refluxedovernight (19 h). The mixture was cooled to room temperature,transferred to a separatory funnel, diluted with ethyl acetate. Anattempt to wash the solution with saturated ammonium chloride resultedin the formation of a precipitate. The precipitate was dissolved withwater and methanol. The resulting mixture was washed with water andbrine, dried over anhydrous sodium sulfate and concentrated. Theresulting residue was purified by silica gel chromatography. Elutionwith 70% ethyl acetate/hexanes followed by 100% ethyl acetate afforded2.7 g (39% yield) of the title compound as a white solid. The titlecompound could be resolved into the corresponding enantiomers A and B asdescribed in Step C variation 1.

EXAMPLES 19-27

The compounds of Examples 19-27, shown in the table provided below, wereprepared in a manner similar to that described in Example 18, Method 1.Example Structure Name (M + H) 19

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4- phenylpiperazine 468 20

7-(3,4-Dichlorophenyl)- 4,7-dihydro-5-methyl-N- propylpyrazolo[1,5-a]pyrimidine-6- carboxamide 365 21

7-(3,4-Dichlorophenyl)- 4,7-dihydro-5-methyl-N- phenyl-pyrazolo[1,5-a]pyrimidine-6- carboxamide 399 22

4-[[7-(2,3- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]morpholine 393 23

7-(2,3-Dichlorophenyl)- 4,7-dihydro-5-methyl-N- propylpyrazolo[1,5-a]pyrimidine-6- carboxamide 365 24

7-(2,3-Dichlorophenyl)- 4,7-dihydro-5-methyl-N- phenylpyrazolo[1,5-a]pyrimidine-6- carboxamide 399 25

7-(2,3-Dichlorophenyl)- 4,7-dihydro-5-methyl-N- (2-phenylethyl)pyrazolo[1,5-a]pyrimidine-6- carboxamide 427 26

7-(3,4-Dichlorophenyl)- 4,7-dihydro-5-methyl-N- (2-phenylethyl)pyrazolo[1,5-a]pyrimidine-6- carboxamide 427 27

7-(3,4-Dichlorophenyl)- 4,7-dihydro-5-methyl-N- 3-pyridinylpyrazolo[1,5-a]pyrimidine-6- carboxamide 400

EXAMPLES 28-82

The compounds of Examples 28-82, shown in the table provided below, wereprepared in a manner similar to that described in Example 18, Method 2.

HPLC resolution of Example 47, Chiralcel OD column (50×500 mm), elutingwith 30% isopropanol/hexanes containing 0.1% triethylamine at 50mL/min), UV detection at 254λ, provided enantiomers A (Example 50) and B(Example 51). Chiralcel OD column (4.6×250 mm) eluting with 30%isopropanol/hexanes containing 0.1% triethylamine at 1 mL/min), UVdetection at 254λ, enantiomer A Rt=9.8 min, >99% ee. Enantiomer BRt=14.2 min, >99% ee.

HPLC resolution of Example 70, Chiralpak AD column (50×500 mm), elutingwith 15% ethanol/hexanes containing 0.1% triethylamine at 50 mL/min), UVdetection at 254λ, provided enantiomers A (Example 72) and B (Example71). Chiralpak AD column (4.6×250 mm) eluting with 15% ethanol/hexanescontaining 0.1% triethylamine at 1 mL/min), UV detection at 254λ,enantiomer A Rt=6.9 min, >99% ee. Enantiomer B Rt=13.4 min, >99% ee.

HPLC resolution of Example 80, Chiralpak AD column (50×500 mm), elutingwith 25% isopropanol/hexanes containing 0.1% triethylamine at 50mL/min), UV detection at 254λ, provided enantiomers A (Example 81) and B(Example 82). Chiralpak AD column (4.6×250 mm) eluting with 30%isopropanol/hexanes containing 0.1% triethylamine at 1 mL/min), UVdetection at 254λ, enantiomer A Rt=5.3 min, >99% ee. Enantiomer B Rt=7.1min, >99% ee. Example Structure Name (M + H) 28

1-[[7-(2,3- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-4-phenyl- piperazine,enantiomer A 468 29

1-[[7-(2,3- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-4-phenyl- piperazine,enantiomer B 468 30

1-[[7-(4-Chlorophenyl)- 4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4- phenylpiperazine 433 31

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5-methyl-N-(phenylmethyl)pyrazolo [1,5-a]pyrimidine-6- carboxamide 413 32

4-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]morpholine 393 33

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-4-methyl- piperazine 406 34

7-(2,3-Dichlorophenyl)- 4,7-dihydro-5-methyl-N- (phenylmethyl)pyrazolo[1,5-a]pyrimidine-6- carboxamide 413 35

7-(4-Chlorophenyl)-4,7- dihydro-5-methyl-N- (phenylmethyl)pyrazolo[1,5-a]pyrimidine-6- carboxamide 378 36

4-[[7-(4-Chlorophenyl)- 4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]morpholine 358 37

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]piperidine 391 38

1-[[7-(2,3- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]piperidine 391 39

7-(3,4-Dichlorophenyl)- 4,7-dihydro-5-methyl-N- (3-phenylpropyl)pyrazolo[1,5-a]pyrimidine-6- carboxamide 441 40

1-[[5-(3,4- Dichlorophenyl)-5,8- dihydro-7-methyl-imidazo[1,2-a]pyrimidin-6- yl]carbonyl]-4-phenyl- piperazine 468 41

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-4-(phenyl- methyl)piperidine481 42

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-4-(phenyl- methyl)piperazine482 43

7-(3,4-Dichlorophenyl)- 4,7-dihydro-5-methyl-N,N- dipropylpyrazolo[1,5-a]pyrimidine-6- carboxamide 407 44

1-[[7-(3-Chlorophenyl)- 4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4- fluorophenyl)piperazine 451 45

1-[[7-(3,4-Difluorophenyl)- 4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4- fluorophenyl)piperazine 453 46

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5- methyl[1,2,4]triazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4- phenylpiperazine 469 47

1-[[7-(2,3- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-4-(4-fluoro- phenyl)piperazine486 48

1-(4-Fluorophenyl)-4- [(4,7-dihydro-5-methyl-7- phenylpyrazolo[1,5-a]pyrimidin-6- yl)carbonyl]piperazine 417 49

1-[[7-(3,4- Dichlorophenyl)-1,2,4,7- tetrahydro-5-methyl-2-oxopyrazolo[1,5- a]pyrimidin-6- yl]carbonyl]-4- phenylpiperazine 484 50

1-[[7-(2,3- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-4-(4-fluoro- phenyl)piperazine,enantiomer A 486 51

1-[[7-(2,3- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-4-(4-fluoro- phenyl)piperazine,enantiomer B 486 52

1-[[5-(2,3- Dichlorophenyl)-5,8- dihydro-7-methyl-imidazo[1,2-a]pyrimidin-6- yl]carbonyl]-4-phenyl- piperazine 468 53

1-(4-Fluorophenyl)-4-[[7- (3-fluorophenyl)-4,7- dihydro-5-methylpyrazolo[1,5- a]pyrimidin-6- yl]carbonyl]-piperazine 435 54

1-[[7-(3,5- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-4-(4-fluoro- phenyl)piperazine486 55

1-[(7-Cyclohexyl-4,7- dihydro-5- methylpyrazolo[1,5- a]pyrimidin-6-yl)carbonyl]-4- phenylpiperazine 405 56

1-[[7-(2,3- Dichlorophenyl)-4,7- dihydro-5-methyl- [1,2,4]triazolo[1,5-a]pyrimidin-6- yl)carbonyl]-4-phenyl- piperazine 469 57

1-[[7-(2,3- Dichlorophenyl)-4,7- dihydro-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-4-phenyl- piperazine 482 58

7-(2,3-Dichlorophenyl)- 4,7-dihydro-5-methyl-6-[(4-phenyl-1-piperazinyl)- carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester 540 59

1-[[4-(2,3- Dichlorophenyl)-4,6,7,8- tetrahydro-2-methyl-1H-pyrimido[1,2-a]pyrimidin- 3-yl]carbonyl]-4-phenyl- piperazine 484 60

4-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-1- piperazinecarboxylic acid1,1-dimethylethyl ester 492 61

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-2,5- dimethylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4- phenylpiperazine 482 62

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5-methyl-2- phenylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4- phenylpiperazine 544 63

7-(3,4-Dichlorophenyl)- 4,7-dihydro-2,5-dimethyl-N-(3-phenylpropyl)pyrazolo [1,5-a]pyrimidine-6- carboxamide 455 64

1-[[7-(2,3- Dichlorophenyl)-2-(1,1- dimethylethyl)-4,7- dihydro-5-methylpyrazolo[1,5- a]pyrimidin-6- yl]carbonyl]-4- phenylpiperazine 52465

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-4-phenyl- piperidine 467 66

7-(3,4-Dichlorophenyl)- 4,7-dihydro-5-methyl-6-[[(3-phenylpropyl)amino]carbonyl]pyrazolo[1,5- a]pyrimidine-3-carboxylicacid ethyl ester 513 67

7-(2,3-Dichlorophenyl)- 4,7-dihydro-5-methyl-6-[(4-phenyl-1-piperazinyl)- carbonyl]pyrazolo[1,5-a]pyrimidine-2-carboxylic acid ethyl ester 540 68

1-[[3-Cyano-7-(2,3- dichlorophenyl)-4,7- dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4- fluorophenyl)piperazine 511 69

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5-methyl-2-(trifluoromethyl)pyrazolo [1,5-a]pyrimidin-6- yl]carbonyl]-4-(4-fluorophenyl)piperazine 554 70

1-[[7-(2,3- Dichlorophenyl)-4,7- dihydro-5-methyl-2-(trifluoromethyl)pyrazolo [1,5-a]pyrimidin-6- yl]carbonyl]-4-(4-fluorophenyl)piperazine 554 71

1-[[7-(2,3- Dichlorophenyl)- 4,7dihydro-5-methyl-2-(trifluoromethyl)pyrazolo [1,5-a]pyrimidin-6- yl]carbonyl]-4-(4-fluorophenyl)piperazine, enantiomer B 554 72

1-[[7-(2,3- Dichlorophenyl)-4,7- dihydro-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-4-(4-fluoro- phenyl)piperazine,enantiomer B 554 73

7-(3,4-Dichlorophenyl)- 4,7-dihydro-5-methyl-N- (3-phenylpropyl)-2-(trifluoromethyl)pyrazolo [1,5-a]pyrimidine-6- carboxamide 509 74

7-(3,4-Dichlorophenyl)-6- [[4-(4-fluorophenyl)-1-pipera-zinyl]carbonyl]-4,7- dihydro-5-methyl- pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester 544 75

(2S)-1-[[7-(2,3- Dichlorophenyl)-4,7- dihydro-5-methyl-2-(trifluoromethyl)pyrazolo [1,5-a]pyrimidin-6- yl]carbonyl]-2-(methoxymethyl)pyrrolidine 489 76

1-[[7-(2,3- Dichlorophenyl)-2-fluoro- 4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4- fluorophenyl)piperazine 504 77

(2S)-1-[[2-Chloro-7-(2,3- dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-2- (methoxymethyl)pyrrolidine455 78

(2S)-1-[[2-Chloro-7-(3,4- dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-2- (methoxymethyl)pyrrolidine455 79

(2S)-1-[[7-(2,3-Dichloro- phenyl)-2-fluoro-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-2- (methoxymethyl)pyrrolidine439 80

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-2,5- dimethylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4- fluorophenyl)piperazine 500 81

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-2,5- dimethylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4- fluorophenyl)piperazine, enantiomer A500 82

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-4-(4-fluoro- phenyl)piperazine,enantiomer B 500

EXAMPLE 837-(2,3-Dichlorophenyl)-4,7-dihydro-5-methyl-N,N-dipropylpyrazolo[1,5-a]pyrimidine-6-carboxamide

Method:

Compound 1: Compound 1 was prepared as described in Example 18, Method 2Step A1 from t-butoxyacetoacetate and dipropylamine.

Title Compound: A mixture of compound 1 (0.2 g, 1.1 mmol),2,3-dichlorobenzaldehyde 2 (0.23 g, 1.3 mmol), piperidine (0.015 ml,0.27 mmol), acetic acid (0.027 mL, 0.27 mmol) and 4A Molecular Sieves(spatula tip) in dimethylformamide (1 mL) was stirred at 70° C.overnight. The mixture was cooled to room temperature. 3-aminopyrazole 3(0.13 g, 1.6 mmol) and sodium acetate (0.28 g, 3.5 mmol) were added andthe mixture was stirred overnight at 70° C. The mixture was cooled toroom temperature, transferred to a separatory funnel, diluted with waterand ethyl acetate, washed with water (a small amount of methanol wasadded to breakup emulsions that formed) and brine, dried over anhydroussodium sulfate and concentrated. The resulting residue was purified bysilica gel chromatography (50% ethyl acetate/hexanes followed by 100%ethyl acetate) to afford 0.10 g (23% yield from compound 1) of the titlecompound. Reverse Phase LC/MS: YMC S5 ODS 4.6×50 mm Ballistic column, UVdetection at 220λ, 4 min. gradient 40-100% Solvent B/A (Solvent A: 10%MeOH/H20 with 0.1% TFA, Solvent B: 90% MeOH/H₂O with 0.1% TFA), 4mL/min. Rt=2.94 min, (96% pure). MS (M+H: 407).

EXAMPLES 84-169

The compounds of Examples 84-169, shown in the table provided below,were prepared in a manner similar to that described in Example 83.

HPLC resolution of Example 84, Chiralpak AS column (50×500 mm), elutingwith 30% isopropanol/hexanes containing 0.1% triethylamine at 50mL/min), UV detection at 254λ, provided enantiomers A (Example 166) andB (Example 167). Chiralpak AS column (4.6×250 mm) eluting with 40%isopropanol/hexanes containing 0.1% triethylamine at 1 mL/min), UVdetection at 254λ, enantiomer A Rt=5.53 min, >99% ee. Enantiomer BRt=12.0 min, 98% ee.

HPLC resolution of Example 165, Chiralpak AD column (50×500 mm), elutingwith 20% isopropanol/hexanes containing 0.1% triethylamine at 50mL/min), UV detection at 254λ provided enantiomers A (Example 169) and B(Example 168). Chiralpak AD column (4.6×250 mm) eluting with 20%isopropanol/hexanes containing 0.1% triethylamine at 1 mL/min), UVdetection at 254λ, enantiomer A Rt=8.3 min, >99% ee. Enantiomer BRt=12.8 min, 98% ee. Example Structure Name (M + H) 84

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4- fluorophenyl)piperazine 486 85

1-[[7-(2,3-Difluorophenyl)- 4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4- fluorophenyl)piperazine 453 86

4-[6-[[4-(4-Fluorophenyl)- 1-piperazinyl]carbonyl]- 4,7-dihydro-5-methylpyrazolo[1,5- a]pyrimidin-7-yl]benzoic acid ester 475 87

1-(4-Fluorophenyl)-4-[[7- (2-fluorophenyl)-4,7- dihydro-5-methylpyrazolo[1,5- a]pyrimidin-6- yl]carbonyl]-piperazine 435 88

1-[[7-(2-Chlorophenyl)- 4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4- fluorophenyl)piperazine 451 89

1-[[7-(2,4- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-4-(4-fluoro- phenyl)piperazine486 90

1-[[4,7-Dihydro-7-(2- methoxyphenyl)-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4- fluorophenyl)piperazine 447 91

1-[[7-(2,3- Dimethoxyphenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-4-(4-fluoro- phenyl)piperazine477 92

1-[[7-(2,4- Dimethoxyphenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-4-(4-fluoro- phenyl)piperazine477 93

1-[[7-(2,5- Dimethoxyphenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-4-(4-fluoro- phenyl)piperazine477 94

1-[[4,7-Dihydro-5-methyl-7-[2-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidin-6-yl]carbonyl]-4-(4- fluorophenyl)piperazine 485 95

1-[[4,7-Dihydro-5-methyl- 7-(2-methylphenyl)pyrazolo [1,5-a]pyrimidin-6-yl]carbonyl]-4-(4- fluorophenyl)piperazine 431 96

1-[[4,7-Dihydro-5-methyl- 7-(3-phenoxyphenyl)pyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4- fluorophenyl)piperazine 509 97

1-[[7-(3,4- Dimethoxyphenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-4-(4-fluoro- phenyl)piperazine477 98

1-[[7-(3,5- Dimethoxyphenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-4-(4-fluoro- phenyl)piperazine477 99

1-[[4,7-Dihydro-5-methyl-7-[3-(phenylmethoxy)phenyl]pyrazolo[1,5-a]pyrimidin-6-yl]carbonyl]-4-(4-fluoro- phenyl)piperazine 523 100 

1-[[4,7-Dihydro-7-(3- hydroxyphenyl)-5-methyl- pyrazolo[1,5-a]pyrimidin-6-yl]carbonyl]-4-(4-fluoro- phenyl)piperazine 433 101 

1-[[4,7-Dihydro-5-methyl-7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidin-6-yl]carbonyl]-4-(4-fluoro- phenyl)piperazine 485 102 

1-[[4,7-Dihydro-5-methyl- 7-(3-methylphenyl)pyrazolo [1,5-a]pyrimidin-6-yl]carbonyl]-4-(4- fluorophenyl)piperazine 431 103 

1-[[7-(4-Cyanophenyl)-4,7- dihydro-5- methylpyrazolo[1,5- a]pyrimidin-6-yl]carbonyl]-4-(4- fluorophenyl)piperazine 442 104 

1-(4-Fluorophenyl)-4-[[7- (4-fluorophenyl)-4,7- dihydro-5-methylpyrazolo[1,5- a]pyrimidin-6- yl]carbonyl]-piperazine 435 105 

N-[4-[6-[[4-(4- Fluorophenyl)-1- piperazinyl]carbonyl]-4,7- dihydro-5-methylpyrazolo[1,5- a]pyrimidin-7- yl]phenyl]acetamide 474 106 

1-[[7-[4-(Dimethyl- amino)phenyl]-4,7- dihydro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl]carbonyl]-4-(4-fluorophenyl)piperazine 460 107 

1-[[4,7-Dihydro-7-(4- methoxyphenyl)-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4- fluorophenyl)piperazine 447 108 

1-[[4,7-Dihydro-5-methyl-7-[4-(phenylmethoxy)phenyl]pyrazolo[1,5-a]pyrimidin-6-yl]carbonyl]-4-(4-fluoro- phenyl)piperazine 523 109 

1-[[7-(4-Butoxyphenyl)- 4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4- fluorophenyl)piperazine 489 110 

1-[[4,7-Dihydro-5-methyl- 7-(2-thienyl)pyrazolo[1,5- a]pyrimidin-6-yl]carbonyl]-4-(4- fluorophenyl)piperazine 423 111 

1-[[4,7-Dihydro-5-methyl- 7-(3-thienyl)pyrazolo[1,5- a]pyrimidin-6-yl]carbonyl]-4-(4- fluorophenyl)piperazine 423 112 

1-[[4,7-Dihydro-5-methyl-7-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidin-6-yl]carbonyl]-4-(4-fluoro- phenyl)piperazine 485 113 

1-[[4,7-Dihydro-5-methyl- 7-(4-methylphenyl)pyrazolo [1,5-a]pyrimidin-6-yl]carbonyl]-4-(4- fluorophenyl)piperazine 431 114 

1-[[4,7-Dihydro-5-methyl- 7-(2-nitrophenyl)pyrazolo [1,5-a]pyrimidin-6-yl]carbonyl]-4-(4- fluorophenyl)piperazine 462 115 

1-[[4,7-Dihydro-5-methyl- 7-(4-nitrophenyl)pyrazolo [1,5-a]pyrimidin-6-yl]carbonyl]-4-(4- fluorophenyl)piperazine 462 116 

1-[[7-(2,6-Difluorophenyl)- 4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4- fluorophenyl)piperazine 453 117 

1-[[7-(2,4-Difluorophenyl)- 4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4- fluorophenyl)piperazine 453 118 

1-[[7-(2,5-Difluorophenyl)- 4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4- fluorophenyl)piperazine 453 119 

1-[[7-(3,5-Difluorophenyl)- 4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4- fluorophenyl)piperazine 453 120 

1-[[4,7-Dihydro-5-methyl-7-[2-(phenylmethoxy)phenyl]pyra-zolo[1,5-a]pyrimidin-6-yl]carbonyl]-4-(4-fluoro- phenyl)piperazine 523 121 

1-[[7-(3,4- Dimethylphenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-4-(4-fluoro- phenyl)piperazine445 122 

1-[[4,7-Dihydro-5-methyl- 7-[4-(trifluoromethoxy)phenyl]py-razolo[1,5-a]pyrimidin-6-yl]carbonyl]-4-(4-fluoro-phenyl)piperazine 501 123 

1-[[4,7-Dihydro-5-methyl- 7-[3-(trifluoromethoxy)phenyl]py-razolo[1,5-a]pyrimidin-6-yl]carbonyl]-4-(4-fluoro-phenyl)piperazine 501 124 

1-[[7-(3-Cyanophenyl)-4,7- dihydro-5- methylpyrazolo[1,5- a]pyrimidin-6-yl]carbonyl]-4-(4- fluorophenyl)piperazine 442 125 

1-[[4,7-Dihydro-7-(3- methoxyphenyl)-5-methyl- pyrazolo[1,5-a]pyrimidin-6-yl]carbonyl]-4-(4-fluoro- phenyl)piperazine 447 126 

1-[[7-(4-Chlorophenyl)- 4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4- fluorophenyl)piperazine 451 127 

1-[[4,7-Dihydro-5-methyl- 7-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4- fluorophenyl)piperazine 509 128 

1-[[4,7-Dihydro-5-methyl- 7-(3-nitrophenyl)pyrazolo [1,5- a]pyrimidin-6-yl]carbonyl]-4-(4- fluorophenyl)piperazine 462 129 

1-[[4,7-Dihydro-5-methyl- 7-(5-methyl-2- furanyl)pyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4- fluorophenyl)piperazine 421 130 

1-[[4,7-Dihydro-7-(1H- imidazol-2-yl)-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4- fluorophenyl)piperazine 407 131 

1-[[4,7-Dihydro-5-methyl- 7-(1H-pyrrol-2- yl)pyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4- fluorophenyl)piperazine 406 132 

1-[[4,7-Dihydro-5-methyl- 7-(2-pyridinyl)pyrazolo [1,5-a]pyrimidin-6-yl]carbonyl]-4-(4- fluorophenyl)piperazine 418 133 

1-[[7-(3-Chloro-4- methoxy-phenyl)-4,7- dihydro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl]carbonyl]-4-(4-fluorophenyl)piperazine 481 134 

1-[[4,7-Dihydro-7-(4- methoxy-1,3-benzodioxol- 6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4- fluorophenyl)piperazine 491 135 

1-[[4,7-Dihydro-7-[5- (hydroxymethyl)-2- furanyl]-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4- fluorophenyl)piperazine 437 136 

1-[[4,7-Dihydro-7-(1H- indol-3-yl)-5- methylpyrazolo[1,5- a]pyrimidin-6-yl]carbonyl]-4-(4- fluorophenyl)piperazine 456 137 

1-[[4,7-Dihydro-5-methyl- 7-(3-pyridinyl)pyrazolo[1,5- a]pyrimidin-6-yl]carbonyl]-4-(4- fluorophenyl)piperazine 418 138 

1-[[4,7-Dihydro-5-methyl- 7-(3-quinolinyl)pyrazolo[1,5- a]pyrimidin-6-yl]carbonyl]-4-(4- fluorophenyl)piperazine 468 139 

1-[[4,7-Dihydro-5-methyl- 7-(4-quinolinyl)pyrazolo[1,5- a]pyrimidin-6-yl]carbonyl]-4-(4- fluorophenyl)piperazine 468 140 

1-[[7-(2,3-Dihydro-1,4- benzodioxin-6-yl)-4,7- dihydro-5-methylpyrazolo[1,5- a]pyrimidin-6- yl]carbonyl]-4-(4-fluorophenyl)piperazine 475 141 

1-[[4,7-Dihydro-5-methyl- 7-(2,3,5-trichloro- phenyl)pyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4- fluorophenyl)piperazine 520 142 

1-[[7-(2,5- Dichlorophenyl)-4,7- dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4- fluorophenyl)piperazine 486 143 

1-(4-Fluorophenyl)-4-[[7- (3-furanyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-piperazine 407 144 

1-[[7-(2-Benzofuranyl)- 4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4- fluorophenyl)piperazine 457 145 

1-[[4,7-Dihydro-5-methyl- 7-(3-methylbenzo[b]thiophen-2-yl)pyrazolo[1,5- a]pyrimidin-6- yl]carbonyl]-4-(4-fluorophenyl)piperazine 487 146 

1-[[4,7-Dihydro-5-methyl- 7-(2-quinolinyl)pyrazolo[1,5- a]pyrimidin-6-yl]carbonyl]-4-(4- fluorophenyl)piperazine 468 147 

1-[[4,7-Dihydro-5-methyl- 7-(2-thiazolyl)pyrazolo[1,5- a]pyrimidin-6-yl]carbonyl]-4-(4- fluorophenyl)piperazine 424 148 

1-(4-Fluorophenyl)-4-[[7- (2-furanyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-piperazine 407 149 

1-[[4,7-Dihydro-7-[3- methoxy-4- (phenylmethoxy)phenyl]-5-methylpyrazolo[1,5- a]pyrimidin-6- yl]carbonyl]-4-(4-fluorophenyl)piperazine 553 150 

1-[[4,7-Dihydro-7-[4- methoxy-3- (phenylmethoxy)phenyl]-5-methylpyrazolo[1,5- a]pyrimidin-6- yl]carbonyl]-4-(4-fluorophenyl)piperazine 553 151 

1-[[4,7-Dihydro-5-methyl- 7-(2-naphthalenyl)pyrazolo [1,5-a]pyrimidin-6-yl]carbonyl]-4-(4- fluorophenyl)piperazine 467 152 

1-[[7-[3,4-Bis(phenyl- methoxy)phenyl]-4,7- dihydro-5-methylpyrazolo[1,5- a]pyrimidin-6- yl]carbonyl]-4-(4-fluorophenyl)piperazine 629 153 

1-[[7-(1,3-Benzodioxol-5- yl)-4,7-dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-4-(4-fluoro- phenyl)piperazine461 154 

1-[[7-[3,5-Bis(trifluoro- methyl)phenyl]-4,7- dihydro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl]carbonyl]-4-(4-fluorophenyl)piperazine 553 155 

1-[[4,7-Dihydro-5-methyl- 7-[5-[1-methyl-3- (trifluoromethyl)-1H-pyrazol-5-yl]-2- thienyl]pyrazolo[1,5- a]pyrimidin-6- yl]carbonyl]-4-(4-fluorophenyl)piperazine 571 156 

1-[[7-(5-Ethyl-2-furanyl)- 4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4- fluorophenyl)piperazine 435 157 

1-[[7-(2,3-Dihydro-5- benzofuranyl)-4,7-dihydro- 5-methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4- fluorophenyl)piperazine 459 158 

1-[[7-(3-Bromophenyl)- 4,7-dihydro-5- methylpyrazolo[1,5- a]pyrimidin-6-yl]carbonyl]-4-(4- fluorophenyl)piperazine 496 159 

1-[[4,7-Dihydro-5-methyl- 7-[4-(1-pyrrolidinyl)- phenyl]pyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4- fluorophenyl)piperazine 486 160 

1-[[4,7-Dihydro-5-methyl- 7-(3-methyl-2- thienyl)pyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4- fluorophenyl)piperazine 437 161 

1-[[4,7-Dihydro-5-methyl- 7-(5-methyl-2- thienyl)pyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4- fluorophenyl)piperazine 437 162 

1-[[7-(1,3-Benzodioxol-4- yl)-4,7-dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-4-(4- fluorophenyl)piperazine461 163 

1-[[7-(5-Chloro-2-thienyl)- 4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4- fluorophenyl)piperazine 457 164 

1-[[7-(3,5- Dimethylphenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-4-(4-fluoro- phenyl)piperazine445 165 

1-[[7-(2,3- Dichlorophenyl)-4,7- dihydro-2,5- dimethylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4- fluorophenyl)piperazine 500 166 

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-4-(4-fluoro- phenyl)piperazine,enantiomer A 486 167 

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-4-(4-fluoro- phenyl)piperazine,enantiomer B 486 168 

1-[[7-(2,3- Dichlorophenyl)-4,7- dihydro-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-4-(4-fluoro- phenyl)piperazine,enantiomer B 500 169 

1-[[7-(2,3- Dichlorophenyl)-4,7- dihydro-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-4-(4-fluoro- phenyl)piperazine,enantiomer A 500

EXAMPLE 1708-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl]carbonyl]-1,4-dioxa-8-azaspiro[4.5]decane

Method:

Compound 1: Compound 1 was prepared as described in Example 16.

Title Compound: Compound 2 (0.068 g, 0.47 mmol) was added to asuspension of compound 1 (0.10 g, 0.32 mmol), EDCI (0.09 g, 0.47 mmol),DMAP(0.004 g, 0.03 mmol) in dichloromethane (1 mL). When LC/MS indicatedthe reaction was complete the mixture was loaded directly onto aWorldwide Monitoring CLEAN-UP CARTRIDGE (silica gel, CUSIL12M6) whichhad been equilibrated with 100% hexanes. Elution with 100% hexanes (40mL), followed by 50% Ethyl acetate/hexanes (40 mL) and 100% ethylacetate (70 mL). The purest fractions (TLC analysis) were combined togive 0.043 g (30% yield) of the title compound as a white solid. ReversePhase LC/MS: YMC S5 ODS 4.6×50 mm Ballistic column, UV detection at220λ, 4 min. gradient 40-100% Solvent B/A (Solvent A: 10% MeOH/H₂₀ with0.1% TFA, Solvent B: 90% MeOH/H₂O with 0.1% TFA), 4 mL/min. Rt=2.12 min,(97% pure). MS (M+H: 449). HMR (DMSO-d₆, 400 MHz, 100° C.) 9.02(1H, bs),7.49(1H, d, J=8 Hz), 7.26(11H, d, J=2 Hz), 7.14(1H, d, J=2 Hz), 6.95(1H,d, J=8 Hz), 6.08(1H, s), 5.55(1H, d, J=2 Hz), 3.84(4H, m), 3.55(2H, m),3.20(2H, m), 1.86(3H, s), 1.37(2H, m), 1.26(2H, m).

EXAMPLES 171-377

The compounds of Examples 171-377, shown in the table provided below,were prepared in a manner similar to that described in Example 170.

HPLC resolution of Example 194, Chiralpak AD column (50×500 mm), elutingwith 30% isopropanol/hexanes containing 0.1% triethylamine at 50mL/min), UV detection at 254λ, provided enantiomers A (Example 250)and B(Example 251). Chiralpak AD column (4.6×250 mm) eluting with 30%isopropanol/hexanes containing 0.1% triethylamine at 1 mL/min), UVdetection at 254λ, enantiomer A Rt=5.32 min, 99% ee. Enantiomer BRt=8.59 min, 98% ee.

HPLC resolution of Example 221, Chiralpak AS column (50×500 mm), elutingwith 50% isopropanol/hexanes containing 0.1% triethylamine at 42mL/min), UV detection at 254λ provided enantiomers A (Example 328) and B(Example 329). Chiralpak AS column (4.6×250 mm) eluting with 30%isopropanol/hexanes containing 0.1% triethyl amine amine at 1 mL/min),UV detection at 254λ, enantiomer A Rt=5.12 min, >99% ee. Enantiomer BRt=8.70 min, >99% ee.

HPLC resolution of Example 288, Chiralpak AD column (50×500 mm), elutingwith 30% isopropanol/hexanes containing 0.1% triethylamine at 50mL/min), UV detection at 254λ provided enantiomers A (Example 376) and B(Example 377). Chiralpak AD column (4.6×250 mm) eluting with 30%isopropanol/hexanes containing 0.1% triethyl amine at 1 mL/min), UVdetection at 254λ, enantiomer A Rt=3.8 min, >99% ee. Enantiomer B Rt=5.6min, >99% ee.

HPLC resolution of Example 333, Chiralpak AD column (50×500 mm), elutingwith 40% isopropanol/hexanes containing 0.1% triethylamine at 50mL/min), UV detection at 254λ, provided enantiomers A (Example 364) andB (Example 365). Chiralpak AD column (4.6×250 mm) eluting with 40%isopropanol/hexanes containing 0.1% triethylamine at 1 mL/min), UVdetection at 254λ, enantiomer A Rt=4.92 min, >99% ee. Enantiomer BRt=8.0 min, >97% ee.

The compound of Example 360 was separated into pure diastereo-isomers bycolumn chromatography (silica gel eluted with 75% ethyl acetate,hexane). The faster eluting isomer is diastereomer 1, the slower elutingisomer is diasteromer 2. When separated by TLC (20% acetone,dichloromethane), diasteriomer 1 has an R_(f) of 0.26 and diastereromer2 has an R_(f) of 0.17. Diastereomer 2 was further separated into purechiral form via preparative chiral HPLC (Chiralpak AD 5 cm×50 cm columneluted with 13% ethanol in hexane with 0.1% TEA at 50 mL/min with UVdetection at 254 nM). The faster eluting isomer is enantiomer A (HPLCretention time 8.1 min, 4.6×250 mm Chiralpak AD column eluted with 10%ethanol, hexane with 0.1% triethylamine at 2 mL/min with UV detection at254 nm) and the slower eluting isomer is enantiomer B (HPLC retentiontime 10.6 min, 4.6×250 mm Chiralpak AD column eluted with 10% ethanol,hexane with 0.1% triethylamine at 2 mL/min with UV detection at 254 nm).Diasteromer 1 can also be further separated into chiral pure form bysimilar methodology as that described for diastereomer 2 above toprovide enantiomers C and D. Example Structure Name (M + H) 171

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methyl-pyrazolo[1,5-a]pyrimidin-6-yl]carbonyl]-4-(2-methoxy- phenyl)piperazine 498 172

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]-pyrimidin-6-yl]carbonyl]- 4-[3-(trifluoromethyl)- phenyl]piperazine 536173

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4- nitrophenyl)piperazine 513 174

1-(4-Acetylphenyl)-4-[[7- (3,4-dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]piperazine 510 175

1-(2-Chlorophenyl)-4-[[7- (3,4-dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1 ,5-a]pyrimidin- 6-yl]carbonyl]piperazine 502 176

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6-yl]- carbonyl]-4-(4-methoxy- phenyl)piperazine 498 177

1-(3,4-Dichlorophenyl)-4- [[7-(3,4-dichloro-phenyl)- 4,7-dihydro-5-methylpyrazolo[1,5- a]pyrimidin-6-yl]- carbonyl]piperazine 537 178

1-(3,5-Dichlorophenyl)-4- [[7-(3,4-dichloro-phenyl)- 4,7-dihydro-5-methylpyrazolo[1,5- a]pyrimidin-6-yl]- carbonyl]piperazine 537 179

1-(4-Chlorophenyl)-4-[[7- (3,4-dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]piperazine 502 180

1-(3-Chlorophenyl)-4-[[7- (3,4-dichlorophenyl)-4,7-dihydro-5-methylpyra- zolo[1,5-a]pyrimidin-6- yl]carbonyl]piperazine 502181

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6-yl]car- bonyl]-4-(3-methoxy- phenyl)piperazine 498 182

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6-yl]car- bonyl]-4-(4-methyl- phenyl)piperazine 482 183

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5a]-pyrimidin-6-yl]car-bonyl]- 4-[4-(trifluoromethyl)- phenyl]piperazine 536184

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6-yl]car- bonyl]-4-(2-fluoro- phenyl)piperazine 486 185

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6-yl]car- bonyl]-4-(3,4-dimethyl- phenyl)piperazine 496 186

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(2- pyrimidinyl)piperazine 470 187

7-(3,4-Dichlorophenyl)-N- [2-[(4-fluoro- phenyl)amino]ethyl]-4,7-dihydro-5-methyl- pyrazolo[1,5-a]pyrimidine-6-carboxamide 460 188

4-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-1- piperazinecarboxylic acidphenylmethyl ester 526 189

7-(3,4-Dichlorophenyl)-N- ethyl-N-[(2- fluorophenyl)methyl]-4,7-dihydro-5-methyl- pyrazolo[1,5-a]pyrimidine-6-carboxamide 459 190

N-[(3-Chloro-4- methoxyphenyl)methyl]-7- (3,4-dichlorophenyl)-4,7-dihydro-5-methyl- pyrazolo[1,5-a]pyrimidine-6-carboxamide 477 191

1-(1,3-Benzodioxol-5- ylmethyl)-4-[[7-(3,4- dichlorophenyl)-4,7-dihydro-5- methylpyrazolo[1,5- a]pyrimidin-6- yl]carbonyl]piperazine 526192

4-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-1- piperazinecarboxylic acid ethyl ester 464193

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(2- pyridinyl)piperazine 469 194

(2S)-1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-2- (methoxymethyl)pyrrolidine 421 195

1-[Bis(4-fluorophenyl)- methyl]-4-[[7-(3,4- dichlorophenyl)-4,7-dihydro-5-methyl- pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]piperazine 594196

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methyl-pyrazolo[1,5-a]pyrimidin-6-yl]car- bonyl]-4-(2-furanyl- carbonyl)piperazine 486 197

1-Cyclohexyl-4-[[7-(3,4- dichlorophenyl)-4,7- dihydro-5-methylpyrazolo[1,5- a]pyrimidin-6- yl]carbonyl]piperazine 474 198

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(2- methoxyethyl)piperazine 450 199

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(9H- fluoren-9-yl)piperazine 556 200

(2R)-1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methyl-pyrazolo[1,5-a]pyrimidin-6-yl]car- bonyl]-2-(methoxy- methyl)pyrrolidine 421 201

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6-yl]car- bonyl]-4-(2,3-dimethyl- phenyl)piperazine 496 202

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6-yl]car- bonyl]-2-piperidine- carboxylic acid ethyl ester463 203

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6-yl]car- bonyl]-N,N-diethyl-3- piperidinecarboxamide 490204

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6-yl]car- bonyl]-3-piperidine- carboxylic acid ethyl ester463 205

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6-yl]car- bonyl]-3-methyl-piperidine 405 206

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6-yl]car- bonyl]-3,5-dimethyl- piperidine 419 207

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6-yl]car- bonyl]-4-hydroxy- piperidine 407 208

4-(4-Chlorophenyl-1-[[7- (3,4-dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyri-midin- 6-yl]carbonyl]-4- hydroxypiperidine 517 209

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6-yl]car- bonyl]-4-piperidine- carboxylic acid ethyl ester463 210

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4- methylpiperidine 405 211

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-1,2,3,4- tetrahydroquinoline 439 212

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]-pyrimidin-6-yl]carbonyl]- decahydroquinoline 445 213

2-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-1,2,3,4- tetrahydroisoquinoline 439 214

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4- propylpiperidine 433 215

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4- (hydroxydiphenylmethyl) piperidine 573216

7-(3,4-Dichlorophenyl)-N- [(2-fluoro-phenyl)methyl]-4,7-dihydro-5-methyl- pyrazolo[1,5-a]pyrimidine-6-carboxamide 431 217

2-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-2,3,4,9- tetrahydro-1H-pyrido[3,4- b]indole478 218

7-(3,4-Dichlorophenyl)- 4,7-dihydro-5-methyl-N- [2-(phenylamino)-ethyl]pyrazolo[1,5-a]pyrimidine-6-carboxamide 442 219

(2S)-1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo]1,5-a]pyrimidin- 6-yl]carbonyl]-2-[(phenyl-amino)methyl]pyrrolidine 482 220

N-Cyclohexyl-7-(3,4- dichlorophenyl)-4,7- dihydro-N,5-dimethyl-pyrazolo[1,5-a]pyrimidine-6-carboxamide 419 221

3[[7(3,4- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]thiazole 395 222

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]pyrrolidine 377 223

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-3,4-dihydro- 1H-indole 425 224

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]azetidine 363 225

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]hexahydro-1H- azepine 405 226

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6-yl]car- bonyl]octahydroazocine 419 227

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-1,2,3,6- tetrahydropyridine 389 228

7-(3,4-Dichlorophenyl)- 4,7dihydro-N,5-dimethyl- N-[2-(2-pyridinyl)-ethyl]pyrazolo[1,5- a]pyrimidine-6- carboxamide 442 229

N-[[7-(3,4- Dichlorophenyl)- 4,7dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-N- (phenylmethyl)glycine ethyl ester 499 230

trans-7-(3,4- Dichlorophenyl)-4,7- dihydro-5-methyl-N-(2-phenylcyclopropyl)pyrazolo [1,5-a]pyrimidine-6- carboxamde 439 231

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-2- methylpyrrolidine 391 232

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-2- methylaziridine 363 233

(2S)-1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-2-[[(2,6-dimethylphenyl)amino]methyl]pyrrolidine 510 234

7-(3,4-Dichlorophenyl)-N- ethyl-4,7-dihydro-5- methyl-N-(4-pyridinylmethyl)pyrazolo [1,5-a]pyrimidine-6- carboxamide 442 235

7-(3,4-Dichlorophenyl)- 4,7-dihydro-N,5-dimethyl- N-[(1R)-1-phenylethyl]pyrazolo[1,5- a]pyrimidine-6- carboxamide 441 236

7-(3,4-Dichlorophenyl)- 4,7-dihydro-N,5-dimethyl- N-[(1 S)-1-phenylethyl]pyrazolo[1,5- a]pyrimidine-6- carboxamide 441 237

6-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-1,3,3- trimethyl-6- azabicyclo[3.2.1]octane459 238

7-(3,4-Dichlorophenyl)-N- (hexahydro-1H-azepin-1- yl)-4,7-dihydro-5-methylpyrazolo[1,5- a]pyrimidine-6- carboxamide 420 239

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]aziridine 349 240

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]octahydro-1H- azonine 433 241

(2R-trans)-1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-2,5- bis(methoxymethyl)-pyrrolidine 465 242

(2S-trans)-1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5-methylpyra-zolo[1,5-a]pyrimidin-6- yl]carbonyl]-2,5-bis- (methoxymethyl)pyrrolidine465 243

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-L-prolinamide 420 244

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-D- prolinamide 420 245

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-2,3-dihydro- 2-methyl-1H-indole 439 246

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-2,3-dihydro- 5-nitro-1H-indole 470 247

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-2,3-dihydro- 6-nitro-1H-indole 470 248

4-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]- thiomorpholine 409 249

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-L-proline methyl ester 435 250

(2S)-1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-2- (methoxymethyl) pyrrolidine,enantiomer A 421 251

(2S)-1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-2- (methoxymethyl)pyrrolidine,enantiomer B 421 252

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-L-proline 1,1- dimethylethyl ester 477 253

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5-methylpyra-zolo[1,5-a]pyrimidin-6- yl]carbonyl]-N-(2- naphthalenyl)-L- prolinamide560 254

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-1,2,3,4- tetrahydro-2- methylquinoline 453255

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-6-fluoro- 1,2,3,4-tetrahydro-2-methylquinoline 471 256

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-L-proline phenylmethyl ester 511 257

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5-methylpyra-zolo[1,5-a]pyrimidin-6- yl]carbonyl]-D-proline phenylmethyl ester 511258

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-4-hydroxy- L-prolinephenylmethyl ester 527 259

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4- fluorophenyl)-2- methylpiperazine 500260

3-Chloro-N-cyclohexyl-7- (3,4-dichlorophenyl)-4,7- dihydro-N,5-dimethyl-pyrazolo[1,5-a]pyri- midine-6-carboxamide 453 261

4-[[3-Chloro-7-(3,4- (3,4-dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]- thiomorpholine 443 262

1-[[3-Chloro-7-(3,4- dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-2,3- dihydro-1H-indole 459 263

1-[[3-Chloro-7-(3,4- dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]hexahydro- 1H-azepine 439 264

1-[[3-Chloro-7-(3,4- dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]- octahydroazocine 453 265

1-[[3-Chloro-7-(3,4- dichlorophenyl)-4,7- dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-1,2,3,6- tetrahydropyridine 423 266

3-Chloro-7-(3,4- dichlorophenyl)-4,7- dihydro-N,5-dimethyl-N-[(1S)-1-phenylethyl]- pyrazolo[1,5-a]pyrimidine- 6-carboxamide 475 267

3-Chloro-7-(3,4- dichlorophenyl)-4,7- dihydro-N,5-dimethyl-N-[(1R)-1-phenylethyl]- pyrazolo[1,5-a]pyrimidine- 6-carboxamide 475 268

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methyl-pyrazolo[1,5-a]pyrimidin-6-yl]- carbonyl]-2-(methoxy- methyl)piperidine 435 269

[(3R)-1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-3- pyrrolidinyl]carbamic acid1,1-dimethylethyl ester 492 270

[(3S)-1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-3- pyrrolidinyl]carbamic acid1,1-dimethylethyl ester 492 271

(3R)-1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-3-(di- methylamino)pyrrolidine420 272

N-[1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-3- pyrrolidinyl]acetamide 434273

N-[1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-3- pyrrolidinyl]-N- methylacetamide 448 274

7-(3,4-Dichlorophenyl)- 4,7-dihydro-5-methyl-N,N- dipentyl-pyrazolo[1,5-a]pyri-midine-6- carboxamide 463 275

7-(3,4-Dichlorophenyl)- N,N-dihexyl-4,7-dihydro- 5-methylpyrazolo[1,5-a]pyrimidine-6- carboxamide 491 276

1-[[3-Chloro-7-(3,4- dichlorophenyl)-4,7- dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]piperidine 425 277

3-Chloro-7-(3- chlorophenyl)-N- cyclohexyl-4,7-dihydro- N,5-dimethyl-pyrazolo[1,5-a]pyrimidine- 6-carboxamide 419 278

(2S)-1-[[3-Chloro-7-(3,4- dichlorophenyl)-4,7- dihydro-5-methyl-pyra-zolo[1,5-a]pyrimidin-6- yl]carbonyl]-2-(methoxy- methyl)pyrrolidine 455279

1-[[3-Chloro-7-(3,4- dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]- decahydroquinoline 479 280

2-[[3-Chloro-7-(3,4- dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-1,2,3,4- tetrahydroisoquinoline473 281

4-[[3-Chloro-7-(3- chlorophenyl)-4,7-dihydro- 5-methyl-pyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]- thiomorpholine 409 282

N-Cyclohexyl-7-(3,4- dichlorophenyl)-4,7- dihydro-N,5-dimethyl-2-(trifluoromethyl)pyrazolo [1,5-a]pyrimidine-6- carboxamide 487 283

7-(3,4-Dichlorophenyl)- N,N-diethyl-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidine-6- carboxamide 379 284

N,N-Dibutyl-7-(3,4- dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidine- 6-carboxamide 435 285

7-(3,4-Dichlorophenyl)- N,N-diheptyl-4,7-dihydro- 5-methyl-pyrazolo[1,5-a]pyrimidine-6- carboxamide 519 286

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]- azacyclotridecane 489 287

9-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]- dodecahydro-1H-fluorene 485288

(2S)-1-[[7-(3,4-Di- chlorophenyl)-4,7-dihydro- 5-methyl-2-(tri-fluoromethyl)pyrazolo- [1,5-a]pyrimidin-6-yl]car- bonyl]-2-(methoxy-methyl)pyrrolidine 489 289

1-[[3-Chloro-7-(3- chlorophenyl)-4,7-dihydro- 5-methy-lpyrazolo[1,5-a]pyrimidin-6-yl]car- bonyl]piperidine 391 290

1-[[3-Chloro-7-(3-chloro- phenyl)-4,7-dihydro-5- methyl-pyrazolo[1,5-a]pyrimidin-6-yl]car- bonyl]hexahydro-1H- azepine 405 291

1-[[3-Chloro-7-(3- chlorophenyl)-4,7-dihydro- 5-methyl-pyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]- octahydroazocine 419 292

1-[[3-Chloro-7-(3- chlorophenyl)-4,7-dihydro- 5-methyl-pyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-1,2,3,6- tetrahydropyridine 389 293

3-Chloro-7-(3- chlorophenyl)-4,7-dihydro- N,5-dimethyl-N-[(1S)-1-phenyl-ethyl]pyrazolo[1,5- a]pyrimidine-6-carboxamide 441 294

(2S)-1-[[3-Chloro-7-(3- chlorophenyl)-4,7-dihydro-5-methyl-pyrazolo[1,5- a]pyrimidin-6- yl]carbonyl]-2-(methoxymethyl)pyrrolidine 421 295

1-[[3-Chloro-7-(3- chlorophenyl)-4,7-dihydro- 5-methyl-pyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]- decahydroquinoline 445 296

2-[[3-Chloro-7-(3- chlorophenyl)-4,7-dihydro- 5-methyl-pyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-1,2,3,4- tetrahydroisoquinoline 439 297

1-[[3-Chloro-7-(2,3- dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]hexahydro- 1H-azepine 439 298

1-[[3-Chloro-7-(2,3- dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-1,2,3,6- tetrahydropyridine 423299

(2S)-1-[[3-Chloro-7-(2,3- dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimi-din- 6-yl]carbonyl]-2- (methoxymethyl)pyrrolidine455 300

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methyl-2-(trifluoro-methyl)pyrazolo[1,5- a]pyrimidin-6- yl]carbonyl]-2,3-dihydro- 1H-indole493 301

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methyl-2-(trifluoro-methyl)pyrazolo[1,5- a]pyrimidin-6- yl]carbonyl]hexahydro-1H- azepine473 302

7-(3,4-Dichlorophenyl)- 4,7-dihydro-N,5-di-methyl-N-[(1S)-1-phenylethyl]-2- (trifluoro- methyl)pyrazolo[1,5-a]pyrimidine-6- carboxamide 509 303

7-(3,4-Dichlorophenyl)- 4,7-dihydro-N,5-dimethyl-N-[(1R)-1-phenylethyl]-2- (trifluoro- methyl)pyrazolo[1,5-a]pyrimidine-6- carboxamide 509 304

7-(3,4-Dichlorophenyl)- 4,7-dihydro-N,N-bis(2- methoxyethyl)-5-methylpyrazolo[1,5- a]pyrimidine-6- carboxamide 439 305

7-(3,4-Dichlorophenyl)- N,N-bis(2-ethoxyethyl)- 4,7-dihydro-5-methylpyrazolo[1,5- a]pyrimidine-6- carboxamide 467 306

7-(3,4-Dichlorophenyl)- 4,7-dihydro-N-(2- methoxyethyl)-N,5-dimethylpyrazolo[1,5- a]pyrimidine-6- carboxamide 395 307

7-(3,4-Dichlorophenyl)- 4,7-dihydro-N-(2- methoxyethyl)-5-methyl-N-propylpyrazolo[1,5- a]pyrimidine-6- carboxamide 423 308

1-[[3-Chloro-7-(2,3- dichlorophenyl)-4,7- dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]piperidine 425 309

2-[[3-Chloro-7-(2,3- dichlorophenyl)-4,7- dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-1,2,3,4- tetrahydroisoquinoline 473 310

1-[[3-Chloro-7-(2,3- dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]- octahydroazocine 453 311

3-Chloro-7-(2,3- dichlorophenyl)-4,7- dihydro-N,5-dimethyl-N-[(1S)-1-phenylethyl]- pyrazolo[1,5-a]pyrimi- dine-6-carboxamide 475 312

3-Chloro-N-cyclohexyl-7- (2,3-dichlorophenyl)-4,7- dihydro-N,5-dimethyl-pyrazolo[1,5-a]pyrim-dine- 6-carboxamide 453 313

3-Chloro-7-(2,3- dichlorophenyl)-4,7- dihydro-5-methyl-N-(phenylmethyl)pyrazolo [1,5-a]pyrimidine-6- carboxamide 447 314

7-(3,4-Dichlorophenyl)-N- ethyl-4,7-dihydro-N-(2- methoxyethyl)-5-methylpyrazolo[1,5- a]pyrimidine-6- carboxamide 409 315

N-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-N- methylglycine ethyl ester 423 316

N-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-N- methylglycine 1,1- dimethylethyl ester451 317

N-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6-yl]car- bonyl]-N-(2-ethoxy-2- oxoethyl)glycine ethyl ester495 318

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-2-(3- pyridinyl)piperidine 468 319

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-1,2,3,4- tetrahydro-6- methylquinoline 453320

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-2- propylpiperidine 433 321

1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-2- [(diethylamino)methyl]piperidine 476 322

7-(3,4-Dichlorophenyl)- 4,7-dihydro-5-methyl-N- (2-phenoxyethyl)-pyrazolo[1,5-a]pyrimidine- 6-carboxamide 443 323

1-[(7-Cyclopropyl-4,7- dihydro-5-methyl- pyrazolo[1,5-a]pyrimidin-6-yl)carbonyl]-4-(4- fluorophenyl)piperazine 381 324

1-[[4,7-Dihydro-5-methyl- 7-(1-methyl- ethyl)pyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4- fluorophenyl)piperazine 383 325

(2S)-1-[[4,7-Dihydro-5- methyl-7-(1-methyl- ethyl)pyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-2-(methoxy- methyl)pyrrolidine 318 326

1-[[4,7-Dihydro-5-methyl- 7-(1-methyl- ethyl)pyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-2,3-dihydro- 1H-indole 322 327

1-[[4,7-Dihydro-5-methyl- 7-(1-methylethyl)pyrazolo [1,5-a]pyrimidin-6-yl]carbonyl]-1,2,3,6- tetrahydropyridine 286 328

3-[]7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]thiazolidine, enantiomer A 395 329

3-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]thiazolidine, enantiomer B 395 330

7-(3,4-Dichlorophenyl)- 4,7-dihydro-N,5-dimethyl- N-(phenyl-methyl)pyrazolo[1,5- a]pyrimidine-6- carboxamide 427 331

7-(3,4-Dichlorophenyl)- 4,7-dihydro-N,5-dimethyl-N-(2-phenylethyl)pyrazolo [1,5-a]pyrimidine-6- carboxamide 441 332

7-(3,4-Dichlorophenyl)- 4,7-dihydro-5-methyl-N- (2-phenylethyl)-N-(phenylmethyl)pyrazolo [1,5-a]pyrimidine-6- carboxamide 517 333

(2S)-1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-2- (phenoxymethyl)pyrrolidine483 334

(2R)-1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-2- (phenoxymethyl)pyrrolidine483 335

(2S)-1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-2-[(4- fluorophenoxy)methyl]-pyrrolidine 501 336

(2R)-1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-2-[(4- fluorophenoxy)methyl]-pyrrolidine 501 337

7-(3,4-Dichlorophenyl)-N- ethyl-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidine-6- carboxamide 351 338

N-Butyl-7-(3,4- dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidine- 6-carboxamide 379 339

7-(3,4-Dichlorophenyl)- 4,7-dihydro-5-methyl-N- pentylpyrazolo[1,5-a]pyrimidine-6- carboxamide 393 340

7-(3,4-Dichlorophenyl)- 4,7-dihydro-N-(2- methoxyethyl)-5-methylpyrazolo[1,5- a]pyrimidine-6- carboxamide 381 341

(2S)-1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-2- (hydroxydiphenylmethyl)pyrrolidine 559 342

(2R)-1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-2- (hydroxydiphenylmethyl)pyrrolidine 559 343

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-2-(3- pyridinyl)pyrrolidine 454 344

(2S)-1-[[7-(2,3- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-2- (methoxymethyl)pyrrolidine421 345

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-2- phenylpyrrolidine 453 346

3-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6-yl]car- bonyl]-2-phenylthiazolidine 471 347

3-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-2- thiazolidinecarboxylic acid methyl ester453 348

7-(3,4-Dichlorophenyl)- 4,7-dihydro-N,5-dimethyl- N-(3-phenyl-propyl)pyrazolo[1,5- a]pyrimidine-6- carboxamide 455 349

7-(3,4-Dichlorophenyl)-N- ethyl-4,7-dihydro-5- methyl-N-(3-phenyl-propyl)pyrazolo[1,5- a]pyrimidine-6- carboxamide 469 350

7-(3,4-Dichlorophenyl)- 4,7-dihydro-5-methyl-N- (3-phenylpropyl)-N-propylpyrazolo[1,5- a]pyrimidine-6- carboxamide 483 351

N-Butyl-7-(3,4-dichloro- phenyl)-4,7-dihydro-5- methyl-N-(3-phenyl-propyl)pyrazolo[1,5- a]pyrimidine-6-carboxamide 497 352

2-(4-Chlorophenyl)-3-[[7- (3,4-dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]thiazolidine 505 353

N-(Cyclopropylmethyl)-7- (3,4-dichlorophenyl)-4,7- dihydro-5-methyl-N-propylpyrazolo[1,5- a]pyrimidine-6- carboxamide 419 354

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methyl-pyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(2,3- dihydro-2-oxo-1H- benzimidazol-1-yl)piperidine 523 355

8-[[7-(2,3-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6-yl]car- bonyl]-1-phenyl-1,3,8- triazaspiro[4.5]decan-4-one537 356

4-(4-Chlorophenyl)- 1-[[7- (3,4-dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]car-bonyl]-1,2,3,6- tetrahydropyridine499 357

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6-yl]car- bonyl]-2-(2-phenyl- ethyl)pyrrolidine 481 358

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6-yl]car- bonyl]-2-(4-methoxy- phenyl)pyrrolidine 483 359

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6-yl]car- bonyl]-2-(2-methoxy- phenyl)pyrrolidine 483 360

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-2-(4-fluoro- phenyl)pyrrolidine 471 361

(3R)-1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-3- phenoxypyrrolidine 469 362

(2S)-2-[(Cyclohexyl- oxy)methyl]-1-[[7-(3,4- dichlorophenyl)-4,7-dihydro-5-methyl- pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]pyrrolidine489 363

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6-yl]car- bonyl]-2-(phenyl- methyl)pyrrolidine 467 364

(2S)-1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-2- (phenoxymethyl)pyrro-lidine, diastereomer A 483 365

(2S)-1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-2- (phenoxymethyl)pyrro-lidine, diastereomer B 483 366

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6-yl]car- bonyl]-2-(3-methoxy- phenyl)pyrrolidine 483 367

(2S)-2-(Butoxymethyl)-1- [[7-(3,4-dichlorophenyl)- 4,7-dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]pyrrolidine 463 368

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-2-(2- thienyl)pyrrolidine 459 369

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-2-(4- pyridinyl)pyrrolidine 454 370

(2S)-1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-2- [(methoxymethoxy)-methyl]pyrrolidine 451 371

(2S)-2-(1H-Benzimidazol- 1-ylmethyl)-1-[[7-(3,4- dichlorophenyl)-4,7-dihydro-5-methyl- pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]pyrrolidine507 372

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-2-(3- furanyl)pyrrolidine 443 373

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-2-(2- pyridinyl)pyrrolidine 454 374

(3S)-1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-3- phenoxypyrrolidine 469 375

(3S)-1-[[7-(3,4- Dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-3- phenoxypyrrolidine 488 376

(2S)-1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methyl-2-(trifluoro-methyl)pyrazolo[1,5- a]pyrimidin-6- yl]carbonyl]-2-(methoxymethyl)pyrrolidine, enantiomer A 489 377

(2S)-1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methyl-2-(trifluoro-methyl)pyrazolo[1,5-a]- pyrimidin-6-yl]carbonyl]-2-(methoxymethyl)pyrro- lidine, enantiomer B 489

EXAMPLE 3781-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl]carbonyl]-L-proline

Method:

Compound 1: Compound 1 (the compound of Example 252) was prepared in amanner similar to that described in Example 170.

Title Compound: Hydrochloric acid (5 mL, 4M in Dioxane) was added tocompound 1 (0.05 g, 0.1 mmol). The resulting mixture was stirred at roomtemperature. After 3 h the mixture was concentrated in vacuo. LC/MSanalysis of the residue indicated that starting material remained.Additional Hydrochloric acid (5 mL, 4M in Dioxane) was added. Theresulting mixture was stirred at room temperature for 7 h. TLC analysisindicated that compound 1 was consumed. The mixture was concentrated invacuo. The residue was purified by preparative reverse phase HPLC togive the title compound as a mixture of diastereomers. LC/MS indicatedthat the compound was still impure (50% pure). Reverse Phase LC/MS: YMCS5 ODS 4.6×50 mm Ballistic, UV detection at 220λ, 4 min. gradient,0-100% Solvent B/A (Solvent A: 10% MeOH/H20 with 0.1% TFA, Solvent B:90% MeOH/H₂O with 0.1% TFA), 4 mL/min. Diastereomer A Rt=3.34,Diastereomer B Rt=3.49 min. MS (M+H: 421). The product was trituratedwith dichlormethane to give 0.014 g (32% yield) of the title compound(85% pure by HPLC). Reverse Phase LC/MS: YMC S5 4.6×50 mm combiscreen,UV detection at 220λ, 4 min. gradient, 0-100% Solvent B/A (Solvent A:10% MeOH/H₂₀ with 0.2% H₃PO₄, Solvent B: 90% MeOH/H₂O with 0.2% H₃PO₄),4 mL/min. Diastereomer A Rt=2.82, Diastereomer B Rt=2.97 min.

EXAMPLE 3797-(3,4-Dichlorophenyl)-4,7-dihydro-N-[(1R)-2,3-dihydro-1H-inden-1-yl]-5-methyl-2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-6-carboxamide

Method:

Compound 1: Compound 1 was prepared as described in Example 17.

Title Compound: To a suspension of polystyrene-supported HOBt resin(NovaBiochem, >1.2 mmol/g, 50 mg, 1.0 eq) in anhydrous CH₂Cl₂ (1.0 mL)was added Compound 1 (47 mg, 2.0 eq), EDCI (23 mg, 2.0 eq), and DMAP(0.7 mg, 0.1 eq). The suspension was shaken vigorously using aVORTEX-GENIE2 for 1 hr. Solvent was then drained and the resin waswashed sequentially with DMF (3×2 mL), THF (3×2 mL), and CH₂Cl₂ (3×2 mL)with vigorous shaking. The resin was resuspended in CH₂Cl₂ (1 mL) and towhich was added (R)-(−)-Aminoindan 2 (0.006 mL, 0.8 eq). The mixture wasshaken for 2 hr. Solvent was drained and the resin was washed withCH₂Cl₂ (3×1 mL) with vigorous shaking. All the washing solutions werecombined and the solvent was removed under reduced pressure. The residuewas purified through a silica gel cartridge eluting with 100% EtOAc togive the title compound as a white solid. Reverse Phase LC/MS: YMC S5ODS 4.6×50 mm Ballistic column, UV detection at 220λ, 4 min. gradient0-100% Solvent B/A (Solvent A: 10% MeOH/H20 with 0.2% H₃PO₄, Solvent B:90% MeOH/H₂O with 0.2% H₃PO₄), 4 mL/min. Rt=2.96 min, (diastereomers,96% pure). MS (M+H): 507.

EXAMPLES 380-391

The compounds of Examples 380-391, shown in the table provided below,were prepared in a manner similar to that described in Example 379.Example Structure Name (M + H) 380

7-(3,4-Dichlorophenyl)-N- (2,3-dihydro-1H-inden-2-yl)-4,7-dihydro-5-methyl- 2-(trifluoro- methyl)pyrazolo[1,5-a]pyrimidine-6- carboxamide 507 381

N-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methyl-2-(trifluoro-methyl)pyrazolo[1,5- a]pyrimidin-6-yl]car- bonyl]-D-phenylalanine methylester 553 382

7-(3,4-Dichlorophenyl)- 4,7-dihydro-5-methyl-N- (1,2,3,4-tetrahydro-1-naphthalenyl)-2-(trifluoro- methyl)pyra-zolo[1,5- a]pyrimidine-6-carboxamide 521 383

7-(3,4-Dichlorophenyl)- 4,7-dihydro-5-methyl-N-[3-(2-oxo-1-pyrrolidinyl) propyl]-2-(trifluoro- methyl)pyrazolo[1,5-a]pyrimidine-6- carboxamide 516 384

7-(3,4-Dichlorophenyl)-N- (2-furanylmethyl)-4,7-dihydro-5-methyl-2-(tri- fluoromethyl)pyra- zolo[1,5-a]pyrimidine-6-carboxamide 471 385

7-(3,4-Dichlorophenyl)-N- [(3,4-dichloro- phenyl)methyl]-4,7-dihydro-5-methyl-2- (trifluoromethyl)pyra- zolo[1,5-a]pyrimidine-6-carboxamide 550 386

7-(3,4-Dichlorophenyl)- 4,7-dihydro-N-[(2R)-2- (methoxymethyl)-1-pyrrolidinyl]-5-methyl-2- (trifluoromethyl)pyra-zolo[1,5-a]pyrimidine-6- carboxamide 504 387

7-(3,4-Dichlorophenyl)- 4,7-dihydro-5-methyl-N- [(tetrahydro-2-furanyl)-methyl]-2-(trifluoro- methyl)pyrazolo[1,5- a]pyrimidine-6-carbox- amide475 388

7-(3,4-Dichlorophenyl)- 4,7-dihydro-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-5- methyl-2-(trifluoro- methyl)pyrazolo[1,5-a]pyrimidine-6- carboxamide 507 389

7-(3,4-Dichlorophenyl)-N- [2-(3,4-dichloro- phenyl)ethyl]-4,7-dihydro-5-methyl-2- (trifluoromethyl)pyra- zolo[1,5-a]pyrimidine-6- carboxamide564 390

7-(3,4-Dichlorophenyl)- 4,7-dihydro-5-methyl-2- (trifluoromethyl)-N-[[4-[(trifluoromethyl)thio]- phenyl]methyl]pyrazolo- [1,5-a]pyrimidine-6-carboxamide 581 391

(2S)-1-[[7-(3,4- Dichlorophenyl)-4,7di- hydro-5-methyl-2-(trifluoro-methyl)pyra- zolo[1,5-a]pyrimidin-6- yl]carbonyl]-2-(1-pyrrolidinylmethyl)- pyrrolidine 666

EXAMPLE 3921-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl]carbonyl]-4-(1-naphthalenylsulfonyl)piperazine

Method:

Compound 1: Compound 1 (the compound of Example 60) was prepared in amanner similar to that described in Example 18, Method 2.

Step A: HCl (4M in dioxane) was added to solid compound 1 (0.53 g, 1.1mmol). A gummy precipitate forms immediately. Dichloromethane was added,the gummy precipitate remained. The solvent was decanted and the residuewas triturated with ethyl acetate (3×), concentrated to give 0.63 g(130% contains residual dioxane) of the hydrochloride salt compound 2 asa light yellow powder. Reverse Phase LC/MS: YMC S5 ODS 4.6×50 mmBallistic column, UV detection at 220λ, 4 min. gradient 40-100% SolventB/A (Solvent A: 10% MeOH/H20 with 0.1% TFA, Solvent B: 90% MeOH/H₂O with0.1% TFA), 4 mL/min. Rt=0.57 min, (92% pure). MS (M+H): 392. Compound 2was used without purification.

Step B: Compound 2 (0.077 g, 0.18 mmol) and compound 3 (0.049 g, 0.22mmol) were suspended in dichloromethane (1 mL). Triethylamine (0.05 mL,0.36 mmol) was added. A clear solution results. TLC after 30 minindicated consumption of starting material. The mixture was loadeddirectly onto a Worldwide Monitoring CLEAN-UP CARTRIDGE (silica,CUSIL12M6) which had been equilibrated with 100% hexanes. Elution with100% hexanes (40 mL), followed by 50% Ethyl acetate/hexanes (40 mL) and100% ethyl acetate (40 mL). The purest fractions (TLC analysis) werecombined to give 0.068 g (65% yield) of the title compound as a whitesolid. Reverse Phase LC/MS: YMC S5 ODS 4.6×50 mm Ballistic column, UVdetection at 220λ, 4 min. gradient 40-100% Solvent B/A (Solvent A: 10%MeOH/H20 with 0.1% TFA, Solvent B: 90% MeOH/H₂O with 0.1% TFA), 4mL/min. Rt=3.46 min, (90% pure). MS (M+H: 582). HMR (CDCl₃, 400 MHz):8.60(1H, d, J=8), 8.05(2H, m), 7.95(1H, m), 7.62(4H, m), 7.35(1H, d, J=2Hz), 7.17(1H, d, J=8 Hz), 7.06(1H, d, J=2 Hz), 6.81(1H, d, J=6 Hz),6.17(1H, m), 5.54(1H, d, J=2 Hz), 3.23(8H, m), 1.86(3H, s).

EXAMPLES 393-396

The compounds of Examples 393-396, shown in the table provided below,were prepared in a manner similar to that described in Example 392.Example Structure Name (M + H) 393

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-[(4- ethylphenyl)sulfonyl]- piperazine 560394

1-[(4-Bromo-5-chloro-2- thienyl)sulfonyl]-4-[[7-(3,4-dichlorophenyl)-4,7- dihydro-5-methyl- pyrazolo[1,5-a]pyrimi-din-6-yl]carbonyl]-piperazine 651 395

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6-yl]car- bonyl]-4-[[2-(trifluoro-methoxy)phenyl]sulfonyl]piperazine 616 396

1-[(5-Chloro-3-methyl- benzo[b]thiophen-2- yl)sulfonyl]-4-[[7-(3,4-dichlorophenyl)-4,7- dihydro-5-methylpyra- zolo[1,5-a]pyrimidin-6-yl]carbonyl]piperazine 637

EXAMPLE 3971-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl]carbonyl]-4-[(3-methoxyphenyl)carbonyl]piperazine

Method:

Compound 1: Compound 1 was prepared as described in Step A of Example392.

Title Compound: Compound 1 (0.062 g, 0.15 mmol) and compound 2 (0.025mL, 0.17 mmol) were suspended in dichloromethane (1 mL). Triethylamine(0.040, 0.29 mmol) was added. A clear solution results. TLC after 30 minindicated consumption of starting material. The mixture was loadeddirectly onto a Worldwide Monitoring CLEAN-UP CARTRIDGE (CUSIL12M6)which had been equilibrated with 100% hexanes. Elution with 100% hexanes(40 mL), followed by 50% Ethyl acetate/hexanes (100 mL) and 100% ethylacetate (100 mL). The purest fractions (TLC analysis) were combined togive 0.022 g (29% yield) of the title compound as a white solid. ReversePhase LC/MS: YMC S5 ODS 4.6×50 mm Ballistic column, UV detection at220λ, 4 min. gradient 40-100% Solvent B/A (Solvent A: 10% MeOH/H20 with0.1% TFA, Solvent B: 90% MeOH/H₂O with 0.1% TFA), 4 mL/min. Rt=2.69 min,(90% pure). MS (M+H: 526).

EXAMPLES 398 AND 399

The compounds of Examples 398 and 399, shown in the table providedbelow, were prepared in a manner similar to that described in Example397. Example Structure Name (M + H) 398

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6-yl]car- bonyl]-4-(1-oxo-3- phenyl-2-propenyl)- piperazine522 399

1 [[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methylpyrazolo[1,5-a]pyrimidin-6-yl]car- bonyl]-4-(4-pyridinylcar- bonyl)piperazine 497

EXAMPLE 4001-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-4,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl]carbonyl]-4-phenylpiperazine

Method:

Compound 1: Compound 1 was prepared as described in Example 18.

Title Compound: Compound 1 (0.08 g, 0.17 mmol) was dissolved indimethylformamide (1.0 mL). NaH (0.005 g, 0.22 mmol, 60% in oil) wasadded and the mixture was stirred for 5 min. Iodomethane (0.012 mL, 0.18mmol) was added. When TLC (5% methanol/dichloromethane) analysisindicated consumption of starting material the reaction was quenchedwith water, diluted with ethyl acetate, transferred to a separatoryfunnel, washed with saturated water and brine, dried over anhydroussodium sulfate and concentrated. The residue was purified by silica gelchromatography eluting with 100% dichloromethane followed by 3%methanol/dichloromethane to provide 0.06 g (75%) of the title compoundas a amber oil. Reverse Phase LC/MS: YMC S5 ODS 4.6×50 mm Ballisticcolumn, UV detection at 220λ, 4 min. gradient 40-100% Solvent B/A(Solvent A: 10% MeOH/H20 with 0.1% TFA, Solvent B: 90% MeOH/H₂O with0.1% TFA), 4 mL/min. Rt=2.99 min, (96% pure). MS (M+H: 482).

EXAMPLES 401-406

The compounds of Examples 401-406, shown in the table provided below,were prepared in a manner similar to that described in Example 400.

HPLC resolution of Example 403, Chiralpak AD column (50×500 mm), elutingwith 35% isopropanol/hexanes containing 0.1% triethylamine at 50mL/min), UV detection at 254λ provided enantiomers A (Example 405) and B(Example 404). Chiralpak AD column (4.6×250 mm) eluting with 30%isopropanol/hexanes containing 0.1% triethylamine at 1 mL/min), UVdetection at 254λ, enantiomer A Rt=14.4 min, >99% ee. Enantiomer BRt=28.7 min, >99% ee. Example Structure Name (M + H) 401

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-4,5- dimethylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]piperidine 405 402

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-4,5- dimethylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4- fluorophenyl)piperazine 500 403

1-[[7-(2,3-Dichloro- phenyl)-4,7-dihydro-4,5- dimethylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4- fluorophenyl)piperazine 500 404

1-[[7-(2,3-Dichloro- phenyl)-4,7-dihydro-4,5- dimethylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4- fluorophenyl)piperazine, enantiomer B500 405

1-[[7-(2,3- Dichlorophenyl)-4,7- dihydro-4,5- dimethylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4- fluorophenyl)piperazine, enantiomer A500 406

1-[[7-(2,3- Dichlorophenyl)-4,7- dihydro-2,4,5- trimethylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4- fluorophenyl)piperazine 514

EXAMPLE 4071-[[7-(2,3-Dichlorophenyl)-4-[(4-fluorophenyl)methyl]-4,7dihydro-2,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl]carbonyl]-4-(4-fluorophenyl)piperazine

Method:

Compound 1: Compound 1 was prepared in a manner similar to thatdescribed in Example 18, Method 2.

Title Compound: Compound 1 (0.10 g, 0.21 mmol) was dissolved indimethylformamide (1.0 mL). NaH (0.007 g, 0.27 mmol, 60% in oil) wasadded and the mixture was stirred for 5 min. 4-Fluorobenzyl chloride(0.028 mL, 0.23 mmol) was added. When TLC (5% methanol/dichloromethane)analysis indicated consumption of starting material the reaction wasquenched with water, diluted with ethyl acetate, transferred to aseparatory funnel, washed with saturated water and brine, dried overanhydrous sodium sulfate and concentrated. The residue was purified bysilica gel chromatography eluting with 100% dichloromethane followed by3% methanol/dichloromethane to provide 0.09 g (69%) of the titlecompound as a amber oil. Reverse Phase LC/MS: YMC S5 ODS 4.6×50 mmBallistic column, UV detection at 220λ, 4 min. gradient 40-100% SolventB/A (Solvent A: 10% MeOH/H20 with 0.1% TFA, Solvent B: 90% MeOH/H₂O with0.1% TFA), 4 mL/min. Rt 3.20 min, (93% pure). MS (M+H: 608).

EXAMPLE 4087-(2,3-Dichlorophenyl)-6-[[4-(4-fluorophenyl)-1-piperazinyl]carbonyl]-2,5-dimethylpyrazolo[1,5-a]pyrimidine-4(7H)-aceticacid ethyl ester

Method:

Compound 1: Compound 1 was prepared in a manner similar to thatdescribed in Example 18, Method 2.

Title Compound: Compound 1 (0.10 g, 0.21 mmol) was dissolved indimethylformamide (1.0 mL). NaH (0.006 g, 0.24 mmol, 60% in oil) wasadded and the mixture was stirred for 5 min. Ethyl bromoacetate (0.029mL, 0.26 mmol) was added. When TLC (5% methanol/dichloromethane)analysis indicated consumption of starting material the reaction wasquenched with water, diluted with ethyl acetate, transferred to aseparatory funnel, washed with saturated water and brine, dried overanhydrous sodium sulfate and concentrated. The residue was purified bysilica gel chromatography eluting with 100% dichloromethane followed by3% methanol/dichloromethane to provide 0.086 g (74%) of the titlecompound as a yellow glass. Reverse Phase LC/MS: YMC S5 ODS 4.6×50 mmBallistic column, UV detection at 220λ, 4 min. gradient 40-100% SolventB/A (Solvent A: 10% MeOH/H20 with 0.1% TFA, Solvent B: 90% MeOH/H₂O with0.1% TFA), 4 mL/min. Rt=3.22 min, (97% pure). MS (M+H: 586).

EXAMPLE 4097-(2,3-Dichlorophenyl)-6-[[4-(4-fluorophenyl)-1-piperazinyl]carbonyl]-N,N,2,5-tetramethylpyrazolo[1,5-a]pyrimidine-4(7H)-acetamide

Method:

Compound 1: Compound 1 was prepared in a manner similar to thatdescribed in Example 18, Method 2.

Title Compound: Compound 1 (0.08 g, 0.16 mmol) was dissolved indimethylformamide (0.8 mL). NaH (0.005 g, 0.19 mmol, 60% in oil) wasadded and the mixture was stirred for 5 min.2-chloro-N,N-dimethylacetamide (0.021 mL, 0.21 mmol) was added. When TLC(5% methanol/dichloromethane) analysis indicated consumption of startingmaterial the reaction was quenched with water, diluted with ethylacetate, transferred to a separatory funnel, washed with water andsaturated brine, dried over anhydrous sodium sulfate and concentrated.The residue was purified by silica gel chromatography eluting with 100%dichloromethane followed by 3% methanol/dichloromethane to provide 0.058g (62%) of the title compound as a yellow oil. Reverse Phase LC/MS: YMCS5 ODS 4.6×50 mm Ballistic column, UV detection at 220λ, 4 min. gradient40-100% Solvent B/A (Solvent A: 10% MeOH/H20 with 0.1% TFA, Solvent B:90% MeOH/H₂O with 0.1% TFA), 4 mL/min. Rt=2.63 min, (93% pure). MS (M+H:585).

EXAMPLE 4101-[[7-(2,3-Dichlorophenyl)-4-[2-(dimethylamino)ethyl]-4,7-dihydro-2,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl]carbonyl]-4-(4-fluorophenyl)piperazine

Method:

Compound 1: Compound 1 was prepared in a manner similar to thatdescribed in Example 18, Method 2.

Title Compound: Compound 1 (0.11 g, 0.21 mmol) was dissolved indimethylformamide (1.0 mL). Sodium hydride (0.054 g, 0.47 mmol, 60% inoil) was added and the mixture was stirred for 5 min.1-Chloro-2-dimethylaminoethane hydrochloride (0.040 g, 0.27 mmol) wasadded. After 25 min the reaction was quenched with water, diluted withethyl acetate, transferred to a separatory funnel, washed with saturatedwater and brine, dried over anhydrous sodium sulfate and concentrated.LC/MS analysis of the residue indicated mostly unreacted startingmaterial. The residue was redissolved in dimethylformamide (1.0 mL),Sodium hydride (0.10 g, 4.2 mmol) was added and the mixture was stirredfor 5 min. 1-Chloro-2-dimethylaminoethane hydrochloride (0.15 g, 1.05mmol) was added. When TLC (5% methanol/dichloromethane) analysisindicated consumption of starting material the reaction was quenchedwith water, diluted with ethyl acetate, transferred to a separatoryfunnel, washed with saturated water and brine, dried over anhydroussodium sulfate and concentrated. The residue was purified by silica gelchromatography eluting with 100% dichloromethane followed by 3%methanol/dichloromethane to provide 0.030 g (25%) of the title compoundas a yellow glass. Reverse Phase LC/MS: YMC S5 ODS 4.6×50 mm Ballisticcolumn, UV detection at 220λ, 4 min. gradient 40-100% Solvent B/A(Solvent A: 10% MeOH/H20 with 0.1% TFA, Solvent B: 90% MeOH/H₂O with0.1% TFA), 4 mL/min. Rt=1.72 min, (92% pure). MS (M+H: 571).

EXAMPLE 4111-[[4-(Cyclopropylmethyl)-7-(2,3-dichlorophenyl)-4,7-dihydro-2,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl]carbonyl]-4-(4-fluorophenyl)piperazine

Method:

Compound 1: Compound 1 was prepared in a manner similar to thatdescribed in Example 18, Method 2.

Title Compound: Compound 1 (0.11 g, 0.21 mmol) was dissolved indimethylformamide (1.0 mL). Sodium hydride (0.006 g, 0.25 mmol, 60% inoil) was added and the mixture was stirred for 5 min.(Bromomethyl)cylcopropane(0.0251 mL, 0.27 mmol) was added. When TLC (5%methanol/dichloromethane) analysis indicated consumption of startingmaterial the reaction was quenched with water, diluted with ethylacetate, transferred to a separatory funnel, washed with saturated waterand brine, dried over anhydrous sodium sulfate and concentrated. Theresidue was purified by silica gel chromatography eluting with 100%dichloromethane followed by 3% methanol/dichloromethane to provide 0.104g (89%) of the title compound as a yellow glass. Reverse Phase LC/MS:YMC S5 ODS 4.6×50 mm Ballistic column, UV detection at 220λ, 4 min.gradient 40-100% Solvent B/A (Solvent A: 10% MeOH/H20 with 0.1% TFA,Solvent B: 90% MeOH/H₂O with 0.1% TFA), 4 mL/min. Rt=2.99 min, (95%pure). MS (M+H: 554).

EXAMPLE 4127-(2,3-Dichlorophenyl)-6-[[4-(4-fluorophenyl)-1-piperazinyl]carbonyl]-N,N,2,5-tetramethylpyrazolo[1,5-a]pyrimidine-4(7H)-carboxamide

Method:

Compound 1: Compound 1 was prepared in a manner similar to thatdescribed in Example 18, Method 2.

Title Compound: Compound 1 (0.22 g, 0.44 mmol) was dissolved intetrahydrofuran (3.0 mL). Sodium hydride (0.106 g, 4.44 mmol, 60% inoil) was added and the mixture was stirred for 5 min.N,N-Dimethylcarbamoyl chloride (0.12 mL, 1.33 mmol) was added. Themixture was stirred overnight. TLC (5% methanol/dichloromethane)analysis indicated consumption of starting material the reaction wasquenched with water, diluted with ethyl acetate, transferred to aseparatory funnel, washed with saturated water and brine, dried overanhydrous sodium sulfate and concentrated. The residue was purified bysilica gel chromatography eluting with 100% dichloromethane followed by3% methanol/dichloromethane to provide 0.22 g (87% yield) of the titlecompound. LC/MS indicated that the compound was impure. The titlecompound was further purified by silica gel chromatoagraphy eluting with10% ethyl acetate/hexanes, followed by 50% ethyl acetate/hexanes and100% ethyl acetate to afford 0.118 g (47% yield) of the title compoundas a white glass. Reverse Phase LC/MS: YMC S5 ODS 4.6×50 mm Ballisticcolumn, UV detection at 220λ, 4 min. gradient 40-100% Solvent B/A(Solvent A: 10% MeOH/H20 with 0.1% TFA, Solvent B: 90% MeOH/H₂O with0.1% TFA), 4 mL/min. Rt=2.45 min, (95% pure). MS (M+H: 571).

EXAMPLE 4131-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-4-methyl-5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-6-yl]carbonyl]-4-(4-fluorophenyl)piperazine

Method:

Step A: Acetic anhydride (0.77 mL, 8.14 mmol) was dropwise added to asolution of 4-(4-fluorophenyl)piperazine 1 (1.17 g, 6.49 mmol) indichloromethane (10 mL). TLC after 30 min. indicated reaction wascomplete. The mixture was transferred to a separatory funnel, washedwith water and brine, dried over anhydrous sodium sulfate andconcentrated to give 1.28 g (89% yield) of compound 2 as a clear solid.Reverse Phase LC/MS: YMC S5 ODS 4.6×50 mm Ballistic column, UV detectionat 220λ, 4 min. gradient 0-100% Solvent B/A (Solvent A: 10% MeOH/H20with 0.1% TFA, Solvent B: 90% MeOH/H₂O with 0.1% TFA), 4 mL/min. Rt=1.58min, (92% pure). MS (M+H: 223). HMR (CDCl₃, 400 MHz): 6.96(2H, m),6.89(2H, m), 3.77(2H, m), 3.62(2H, m), 3.07(4H, m), 2.14(3H, s).Compound 2 was used without further purification in the next step.

Step B: Lithium hexamethyldisilylazide (6.1 mL, 6.1 mmol, 1M intetrahydrofuran) was dropwise added to a −78° C. solution of compound 2(1.22 g, 5.5 mmol) in tetrahydrofuran (25 mL). After 40 min.2,2,2-trifluoroethyl trifluoroacetate (0.9 mL, 6.6 mmol) was added tothe yellow solution. The reaction turned from yellow to clear. After anadditional 10 min. the cooling bath was removed and the mixture wasallowed to warm to room temperature. After 30 min. more the reaction wasquenched with saturated ammonium chloride, diluted with ethyl acetate,transferred to a separatory funnel, washed with saturated ammoniumchloride, water and brine, dried over anhydrous sodium sulfate andconcentrated onto enough silica gel such that a free flowing powder wasobtained. The resulting powder was loaded onto a chromatography columnprepacked with silica gel and 30% ethylacetate/hexanes. Elution with 30%ethyl acetate/hexanes gave 0.998 g (57% yield) of compound 3 as a yellowsolid. Reverse Phase LC/MS: YMC S5 ODS 4.6×50 mm Ballistic column, WVdetection at 220λ, 4 min. gradient 40-100% Solvent B/A (Solvent A: 10%MeOH/H20 with 0.1% TFA, Solvent B: 90% MeOH/H₂O with 0.1% TFA), 4mL/min. Rt=2.87 min, (90% pure). MS (M+H: 319). HMR (CDCl₃, 400 MHz):(note compound exists in the enol form) 7.00(2H, m), 6.90(2H, m),5.80(1H, s), 3.79(4H, m), 3.13(4H, m).

Step C: Compound 3 and compound 4 were condensed as described in Example18, Method 2 Step B, to provide compound 5. Compound 5 was used in thenext step without further purification.

Step D: Compound 5 and compound 6 were condensed as described in Example18, Method 2 Step C1, to afford compound 7. Reverse Phase LC/MS of crude6: YMC S5 ODS 4.6×50 mm Ballistic column, UV detection at 220λ, 4 min.gradient 0-100% Solvent B/A (Solvent A: 10% MeOH/H20 with 0.1% TFA,Solvent B: 90% MeOH/H₂O with 0.1% TFA), 4 mL/min. Rt=4.12 min, (58%pure). MS (M+H: 540). Compound 7 was purified by silica gelchromatography eluting with 20-50% ethyl acetate/hexanes followed byrecrystallization from ethyl acetate/hexanes to give 0.084 g (6% yield)of compound 7 as a white solid. Reverse Phase LC: YMC S5 ODS 4.6×50 mmBallistic column, UV detection at 220λ, 4 min. gradient 0-100% SolventB/A (Solvent A: 10% MeOH/H20 with 0.2% H₃PO₄, Solvent B: 90% MeOH/H₂Owith 0.2% H₃PO₄), 4 mL/min. Rt=4.15 min, (92% pure).

Step E: Compound 7 (0.08 g, 0.14 mmol) was dissolved indimethylformamide (1.0 mL). NaH (0.005 g, 0.19 mmol, 60% in oil) wasadded and the mixture was stirred for 305 min. Iodomethane (0.010 mL,0.16 mmol) was added. The mixture was stirred for 2 h and then quenchedwith saturated ammonium chloride, diluted with ethyl acetate,transferred to a separatory funnel, washed with saturated water andbrine, dried over anhydrous sodium sulfate and concentrated. The residuewas purified by preparative reverse phase HPLC:YMC S5 ODS 20×100 mmBallistic column, UV detection at 220λ, 10 min. gradient 30-100% SolventB/A (Solvent A: 10% MeOH/H20 with 0.1% TFA, Solvent B: 90% MeOH/H₂O with0.1% TFA), 20 mL/min. Rt=10.6 min, to provide 0.037 g (45%) of the titlecompound. Reverse Phase LC/MS: YMC S5 ODS 4.6×50 mm Ballistic column, UVdetection at 220λ, 4 min. gradient 0-100% Solvent B/A (Solvent A: 10%MeOH/H20 with 0.1% TFA, Solvent B: 90% MeOH/H₂O with 0.1% TFA), 4mL/min. Rt=3.83 min. MS (M+H: 568). Reverse Phase LC: YMC S5 ODS 4.6×50mm Ballistic column, UV detection at 220λ, 4 min. gradient 0-100%Solvent B/A (Solvent A: 10% MeOH/H20 with 0.2% H₃PO₄, Solvent B: 90%MeOH/H₂O with 0.2% H₃PO₄), 4 m-L/min. Rt=4.37 min., 89% pure.

EXAMPLES 414-421

The compounds of Examples 414-421, shown in the table provided below,were prepared in a manner similar to that described in Example 413.

HPLC resolution of Example 416, Chiralpak AD column (50×500 mm), elutingwith 50% isopropanol/hexanes containing 0.1% triethylamine at 50mL/min), UV detection at 254λ, provided enantiomers A (Example 418) andB (Example 417). Chiralpak AD column (4.6×250 mm) eluting with 50%isopropanol/hexanes containing 0.1% triethylamine at 1 mL/min), UVdetection at 254λ, enantiomer A Rt=14.4 min, 89% ee. Enantiomer BRt=28.7 min, 87% ee. Example Structure Name (M + H) 414

1-[[7-(2,3- Dichlorophenyl)-4,7- dihydro-5-(trifluoro-methyl)pyrazolo[1,5- a]pyrimidin-6-yl]car- bonyl]-4-(4-fluoro-phenyl)piperazine 554 415

1-[[7-(2,3-Dichloro- phenyl)-4,7-dihydro-2- methyl-5-(trifluoro-methyl)pyrazolo[1,5- a]pyrimidin-6-yl]car- bonyl]-4-(4-fluoro-phenyl)piperazine 554 416

1-[[7-(2,3-Dichloro- phenyl)-4,7-dihydro-2,4- dimethyl-5-(trifluoro-methyl)pyrazolo[1,5- a]pyrimidin-6- yl]carbonyl]-4-(4-fluorophenyl)piperazine 568 417

1-[[7-(2,3-Dichloro- phenyl)-4,7-dihydro-2,4- dimethyl-5-(trifluoro-methyl)pyrazolo[1,5- a]pyrimidin-6-yl]car- bonyl]-4-(4-fluoro-phenyl)piperazine, enantiomer B 568 418

1-[[7-(2,3-Dichloro- phenyl)-4,7-dihydro-2,4- dimethyl-5-(trifluoro-methyl)pyrazolo[1,5- a]pyrimidin-6-yl]car- bonyl]-4-(4-fluoro-phenyl)piperazine, enantiomer A 568 419

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- (trifluoromethyl)pyrazolo[1,5-a]pyrimidin-6-yl]car- bonyl]-4-(4-fluoro- phenyl)piperazine 540 420

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-2- methyl-5-(trifluoro-methyl)pyrazolo[1,5- a]pyrimidin-6-yl]car- bonyl]-4-(4-fluoro-phenyl)piperazine 554

EXAMPLE 4211-[[1-Benzoyl-7-(2,3-dichlorophenyl)-1,2,4,7-tetrahydro-5-methyl-2-oxopyrazolo[1,5-a]pyriridin-6-yl]carbonyl]-4-phenylpiperazine

Method:

Compound 1: Compound 1 was prepared in manner similar to that describedin Example 18, Method 2.

Title Compound: Benzoyl chloride (0.007 mL, 0.06 mmol) and pyridine(0.008 mL, 0.10 mmol) were added to a 0° C. solution of compound 1 (0.08g, 0.17 mmol) in dichloromethane (5 mL). After 1 h, TLC indicated thereaction was complete. The reaction was quenched with methanol andconcentrated. The residue was purified by silica gel chromatographyeluting with 80% ethyl acetate/hexanes to afford 0.024 g (81%) of thetitle compound as a white solid. Reverse Phase LC/MS: YMC S5 ODS 4.6×50mm Ballistic column, UV detection at 220λ, 4 min. gradient 0-100%Solvent B/A (Solvent A: 10% MeOH/H20 with 0.1% TFA, Solvent B: 90%MeOH/H₂O with 0.1% TFA), 4 mL/min. Rt=4.05 min, (86% pure). (M+H: 588).HMR (CDCl₃, 400 MHz): 8.08(1H, s), 8.06(1H, s), 7.51(1H, m), 7.37(2H, t,J=8 Hz), 7.28(1H, m), 7.18(2H, m), 7.08(1H, m), 6.9-6.7(3H, m), 6.45(1H, bs), 5.60(1H, bs), 4.15-2.8 (6H, m), 2.20(1H, bs), 1.88(3H, s),1.45(1H, bs).

EXAMPLES 422-431

The compounds of Examples 422-431, shown in the table provided below,were prepared in a manner similar to that described in Example 421.Example Structure Name (M + H) 422

1-[[1-Benzoyl-7-(3,4- dichlorophenyl)-1,2,4,7- tetrahydro-5-methyl-2-oxopyrazolo[1,5- a]pyrimidin-6-yl]car- bonyl]-4-phenyl-piperazine 588423

1-[[1-Acetyl-7-(3,4- dichlorophenyl)-1,2,4,7- tetrahydro-5-methyl-2-oxopyrazolo[1,5- a]pyrimidin-6-yl]car- bonyl]-4-phenyl-piperazine 526424

1-[[7-(3,4-Dichloro- phenyl)-1,2,4,7-tetrahydro- 5-methyl-2-oxo-1-(1-oxobutyl)-pyrazolo[1,5- a]pyrimidin-6- yl]carbonyl]-4- phenylpiperazine554 425

1-[[1-(Cyclopropyl- carbonyl)-7-(3,4- dichlorophenyl)-1,2,4,7-tetrahydro-5-methyl-2- oxopyrazolo[1,5- a]pyrimidin-6-yl]car-bonyl]-4-phenyl-piperazine 552 426

1-[[1-(Cyclopropyl- carbonyl)-7-(2,3- dichlorophenyl)-1,2,4,7-tetrahydro-5-methyl-2- oxopyrazolo[1,5- a]pyrimidin-6-yl]car-bonyl]-4-(4-fluoro- phenyl)piperazine 570 427

1-[[7-(2,3-Dichloro- phenyl)-1,2,4,7-tetra- hydro-5-methyl-1-(3-methyl-1-oxobutyl)-2- oxopyra-zolo[1,5-a]pyrimidin-6-yl]carbonyl]-4-(4-fluorophenyl)-piperazine 586 428

1-[[7-(2,3-Dichloro- phenyl)-(2,2-dimethyl-1- oxopropyl)-1,2,4,7-tetrahydro-5-methyl-2- oxopyrazolo[1,5- a]pyrimidin-6-yl]carbonyl]-4-phenyl-piperazine 568 429

1-[[1-(Cyclopropyl- carbonyl)-7-(3,4- dichlorophenyl)- 1,2,4,7-tetrahydro-5-methyl-2- oxopyrazolo[1,5- a]pyrimidin-6-yl]car-bonyl]-4-(4-fluoro- phenyl)piperazine 570 430

1-[[1-(Cyclobutyl- carbonyl)-7-(3,4- dichlorophenyl)-1,2,4,7-tetrahydro-5-methyl-2- oxopyrazolo[1,5- a]pyrimidin-6-yl]car-bonyl]-4-(4-fluoro- phenyl)piperazine 584 431

1-[[7-(3,4-Dichloro- phenyl)-1,2,4,7-tetrahydro- 5-methyl-1-(2-methyl-1-oxopropyl)-2- oxopyrazolo[1,5- a]pyrimidin-6-yl]car- bonyl]-4-(4-fluoro-phenyl)piperazine 572

EXAMPLE 4321-[[7-(2,3-Dichlorophenyl)-1,2,4,7-tetrahydro-5-methyl-1-[(1-methylethyl)sulfonyl]-2-oxopyrazolo[1,5-a]pyrimidin-6-yl]carbonyl]-4-phenylpiperazine

Method:

Compound 1: Compound 1 was prepared in a manner similar to thatdescribed in Example 18, Method 2.

Title Compound: Isopropylsulfonyl chloride (0.11 mL, 0.97 mmol) andpyridine (0.12 mL, 1.46 mmol) were added to a 0° C. solution of compound1 (0.234 g, 0.487 mmol) in dichloromethane (10 mL). The resultingmixture was allowed to warm to room temperature. After 5 h, TLCindicated the reaction was complete. The reaction was quenched withmethanol and concentrated. The residue was purified by silica gelchromatography eluting with 5% methanol/ethyl acetate to afford 0.095 g(33%) of the title compound as a pale yellow solid. Reverse Phase LC/MS:YMC S5 ODS 4.6×50 mm Ballistic column, UV detection at 220λ, 4 min.gradient 0-100% Solvent B/A (Solvent A: 10% MeOH/H20 with 0.1% TFA,Solvent B: 90% MeOH/H₂O with 0.1% TFA), 4 mL/min. Rt=3.57 min, (92%pure). (M+H: 590).

EXAMPLE 4331-[[7-(3,4-Dichlorophenyl)-1,2,4,7-tetrahydro-5-methyl-1-[(1-methylethyl)sulfonyl]-2-oxopyrazolo[1,5-a]pyrimidin-6-yl]carbonyl]-4-(4-fluorophenyl)piperazine

The title compound was prepared in a manner similar to that described inExample 432. (M+H) 608.

EXAMPLE 4347-(2,3-Dichlorophenyl)-4,7-dihydro-5-methyl-N-(1-methylethyl)-2-oxo-6-[(4-phenyl-1-piperazinyl)carbonyl]pyrazolo[1,5-a]pyrimidine-1(2H)-carboxamide

Method:

Compound 1: Compound 1 was prepared in a manner similar to thatdescribed in Example 18, Method 2.

Title Compound: Isopropyl isocyanate (0.034 mL, 0.35 mmol) and pyridine(0.057 mL, 0.706 mmol) were added to a 0° C. solution of compound 1(0.170 g, 0.350 mmol) in dichloromethane (50 mL). The resulting mixturewas allowed to warm to room temperature. After 5 h, TLC indicated thereaction was complete. The reaction was quenched with methanol andconcentrated. The residue was purified by silica gel chromatographyeluting with 75% ethyl acetate/hexanes to afford 0.027 g (13%) of thetitle compound as a white solid. Reverse Phase LC/MS: YMC S5 ODS 4.6×50mm Ballistic column, UV detection at 220λ, 4 min. gradient 0-100%Solvent B/A (Solvent A: 10% MeOH/H20 with 0.1% TFA, Solvent B: 90%MeOH/H₂O with 0.1% TFA), 4 mL/min. Rt=3.68 min, (95% pure). (M+H: 569).

EXAMPLES 435 AND 436

The compounds of Examples 435 and 436, shown in the table providedbelow, were prepared in a manner similar to that described in Example434. Example Structure Name (M + H) 435

7-(2,3-Dichlorophenyl)- 4,7-dihydro-N,5-dimethyl- 2-oxo-6-[(4-phenyl-1-piperazinyl)- carbonyl]pyrazolo[1,5- a]pyrimidine-1(2H)- carboxamide 541436

7-(2,3-Dichlorophenyl)- 4,7-dihydro-5-methyl-2- oxo-6-[(4-phenyl-1-piperazinyl)carbonyl]- pyrazolo[15-a]pyrimidine-1(2H)-carbox- amide 527

EXAMPLE 4377-(3,4-Dichlorophenyl)-6-[[4-(4-fluorophenyl)-1-piperazinyl]carbonyl]-4,7-dihydro-N,N,5-trimethyl-2-oxopyrazolo[1,5-a]pyrimidine-1(2H)-carboxamide

Method:

Compound 1: Compound 1 was prepared in a manner similar to thatdescribed in Example 18, Method 2.

Title Compound: Dimethylcarbamoyl chloride (0.10 mL, 1.1 mmol) was addedto a 0° C. solution of compound 1 (0.52 g, 1.0 mmol) in pyridine (5 mL).The resulting mixture was stirred at 0° C. for 30 min., the cooling bathwas removed, and the mixture was concentrated. The residue was dissolvedin ethyl acetate and washed with water and brine, dried over anhydroussodium sulfate and concentrated. The residue was purified by silica gelchromatography eluting with 5% methanol/ethyl acetate to afford 0.038 g(6%) of the title compound as a white solid. Reverse phase LC/MS: YMC S5TurboPack Pro 4.6×33 column, UV detection at 220λ, 2 min gradient 0-100%Solvent B/A (Solvent A: 10% MeOH/H₂O with 0.1% TFA, Solvent B: 90%MeOH/H₂O with 0.1% TFA), 4 mL/min. Rt=1.97 min, 92% pure). MS (M+H:573).

EXAMPLE 4381-[[1-(3-Butenyl)-7-(3,4-dichlorophenyl)-1,2,4,7-tetrahydro-5-methyl-2-oxopyrazolo[1,5-a]pyrimidin-6-yl]carbonyl]-4-(4-fluorophenyl)piperazine

Method:

Compound 1: Compound 1 was prepared in a manner similar to thatdescribed in Example 18, Method 2.

Title Compound: (Bromomethyl)cyclopropane (0.246 mL, 1.82 mmol) wasadded to a mixture of compound 1 (0.831 g, 1.66 mmol) and potassiumcarbonate (g, mmol) in dimethylformamide (10 mL). The resulting mixturewas allowed to stir at room temperature for 4 h. The reaction wasdiluted with ethyl acetate, transferred to a separatory funnel, washedwith water and brine, dried over anhydrous sodium sulfate andconcentrated. The residue was purified by silica gel chromatographyeluting with 5% methanol/ethyl acetate to afford 0.030 g (3%) of thetitle compound. Reverse Phase LC/MS: YMC S5 ODS 4.6×50 mm Ballisticcolumn, UV detection at 220λ, 4 min. gradient 0-100% Solvent B/A(Solvent A: 10% MeOH/H20 with 0.1% TFA, Solvent B: 90% MeOH/H₂O with0.1% TFA), 4 mL/min. Rt=2.99 min, (87% pure). (M+H: 556).

EXAMPLES 439 AND 4401-[[7-(3,4-Dichlorophenyl)-1,2,4,7-tetrahydro-tetrahydro-5-methyl-2-oxo-1-(2,2,2-trifluoroethyl)pyrazolo-[1,5-a]pyrimidin-6-yl]carbonyl]-4-(4-fluorophenyl)piperazine1-[[7-(3,4-Dichlorophenyl)-1,2,4,7tetrahydro-5-methyl-2-oxo-1,4-bis(2,2,2-trifluoroethyl)pyrazolo-[1,5-a]pyrimidin-6-yl]carbonyl]-4-(4-fluorophenyl)piperazine

Method:

Compound 1: Compound 1 was prepared in a manner similar to thatdescribed in Example 18, Method 2.

Title Compounds: 2,2,2-trifluoroethyl trifluormethanesulfonate (0.49 g,2.1 mmol) was added to a solution of compound 1 (0.967 g, 1.93 mmol) indimethylformamide (10 mL). Sodium hydride (0.12 g, 2.89 mmol) was added.TLC (10% methanol/ethyl acetate) indicated consumption of compound 1.The resulting mixture was was diluted with ethyl acetate, transferred toa separatory funnel, washed with water and brine, dried over anhydroussodium sulfate and concentrated. The residue was purified by silica gelchromatography eluting with 100% ethyl acetate followed by 10%methanol/ethyl acetate to give a mixture of the title compounds. Thetitle compounds were separated by preparative reverse phase HPLC YMC S5ODS 20×100 mm column, 25 mL/min, 15 minute gradient eluting with50%-100% solvent B/A (Solvent A: 10% MeOH/H20 with 0.1% TFA, Solvent B:90% MeOH/H₂O with 0.1% TFA). Compound of Example 439 Rt=11.05 min,Compound of Example 440 Rt=11.88 min. Compound of Example 439: Reversephase LC/MS: YMC S5 4.6×50 Ballistic column, UV detection at 220λ, 4 mingradient 0-100% Solvent B/A (Solvent A: 10% MeOH/H₂O with 0.1% TFA,Solvent B: 90% MeOH/H₂O with 0.1% TFA), 4 mL/min. Rt=2.87 min, 95%pure). MS (M+H: 584). Compound of Example 440: Reverse phase LC/MS: YMCS5 4.6×50 Ballistic column, UV detection at 220λ, 4 min gradient 0-100%Solvent B/A (Solvent A: 10% MeOH/H₂O with 0.1% TFA, Solvent B: 90%MeOH/H₂O with 0.1% TFA), 4 mL/min. Rt=3.25 min, 85% pure). MS (M+H:666).

EXAMPLE 4417-(3,4-Dichlorophenyl)-6-[[4-(4-fluorophenyl)-1-piperazinyl]carbonyl]-4,7-dihydro-5-methyl-2-oxopyrazolo[1,5-a]pyrimidine-1(2H)-carboxylicacid 1-methylethyl ester

Method:

Compound 1: Compound 1 was prepared in a manner similar to thatdescribed in Example 18, Method 2.

Title Compound: Isopropyl chloroformate (1.0 mL, 1.0 mmol, 1M intoluene) was added to a 0° C. solution of compound 1 (0.46 g, 0.92 mmol)in pyridine (5 mL). The resulting mixture was stirred at 0° C. for 30min., the cooling bath was removed. After 2 h methanol was added toquench the reaction and the mixture was concentrated. The residue waspurified by silica gel chromatography eluting with 5% methanol/ethylacetate to afford 0.057 g (11%) of the title compound as a light pinksolid. Reverse phase LC/MS: YMC S5 ODS 4.6×50 column, UV detection at220λ, 4 min gradient 0-100% Solvent B/A (Solvent A: 10% MeOH/H₂O with0.1% TFA, Solvent B: 90% MeOH/H₂O with 0.1% TFA), 4 mL/min. Rt=3.67 min,95% pure). (M+H: 573).

EXAMPLE 4421-[(4,7-Dihydro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)carbonyl]-4-phenylpiperazine

Method:

Compound 1: Compound 1 was prepared in a manner similar to thatdescribed in Example 18, Method 2.

Step A: Compound 2 (0.6 mL, 4.4 mmol) and acetic anhydride (0.83 mL, 8.8mmol) were added to a solution of compound 1 (0.72 g, 2.9 mmol) indimethylformamide (10 mL). The mixture was allowed to stir overnight,poured into water, extracted with dichloromethane. The extracts werecombined, dried over anhydrous sodium sulfate and concentrated. Theresidue was purified by silica gel chromatography eluting with 50% ethylacetate/hexanes to 100% ethyl acetate/hexanes to give 0.290 g (38%yield) of compound 3 as a colorless syrup. (M+H: 259).

Step B: Condensation of compound 3 and compound 4 as described inExample 18, Method 2 Step C provided the title compound. Reverse PhaseLC/MS: YMC S5 ODS 4.6×50 mm Ballistic column, UV detection at 220λ, 4min. gradient 0-100% Solvent B/A (Solvent A: 10% MeOH/H20 with 0.1% TFA,Solvent B: 90% MeOH/H₂O with 0.1% TFA), 4 mL/min. Rt=1.96 min, (87%pure). (M+H: 323).

EXAMPLE 4437-(3,4-Dichlorophenyl)-6-[[4-(4-fluorophenyl)-1-piperazinyl]carbonyl]-4,7-dihydro-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylicacid

Method:

Compound 1: Compound 1 was prepared in a manner similar to thatdescribed in Example 18, Method 2.

Step A: Lithium hydroxide (0.43 g, 1.8 mmol) was dissolved in water (3mL) and added slowly to a room temperature solution of compound 1 intetrahydofuran (9 mL). The resulting mixture was stirred at roomtemperature for 3 h. TLC indicated that all of compound 1 had beenconsumed. The mixture was quenched by the addition of acidic Dowexresin. The resin was filtered off. The filtrate was diluted with ethylacetate, washed with water and brine, dried over anhydrous sodiumsulfate and concentrated to give 0.41 g (86% yield) of compound 2 as alight yellow solid. Reverse phase LC/MS: YMC S5 ODS 4.6×50 column, UVdetection at 220λ, 4 min gradient 0-100% Solvent B/A (Solvent A: 10%MeOH/H₂O with 0.1% TFA, Solvent B: 90% MeOH/H₂O with 0.1% TFA), 4mL/min. Rt=3.37 min, 96% pure). MS (M+H: 530).

Step B: EDCI (0.025 g, 0.13 mmol), DMAP (0.003 g, 0.02 mmol) were addedto a solution of compound 2 (0.0508 g, 0.1 mmol) and diethylamine (0.014mL, 0.13 mmol) in dichloromethane (3 mL). The mixture was stirredovernight. TLC indicated some starting material remained. The solventwas removed under reduced pressure. The resulting residue was purifiedby silica gel chromatography eluting with 5% methanol/ethyl acetate togive the title compound as a white solid. Reverse phase LC/MS: YMC S54.6×50 Ballistic column, UV detection at 220λ, 4 min gradient 0-100%Solvent B/A (Solvent A: 10% MeOH/H₂O with 0.1% TFA, Solvent B: 90%MeOH/H₂O with 0.1% TFA), 4 mL/min. Rt=3.74 min, 91% pure). MS (M+H:585).

EXAMPLES 444-449

The compounds of Examples 445-450, shown in the table provided below,were prepared in a manner similar to that described in Example 443.Example Structure Name (M + H) 444

7-(3,4-Dichlorophenyl)- N,N-diethyl-6-[[4-(4- fluorophenyl)-1-piperazinyl]carbonyl]-4,7- dihydro-5- methylpyrazolo[1,5-a]pyrimidine-2- carboxamide 585 445

7-(3,4-Dichlorophenyl)-6- [[4-(4-fluorophenyl)-1-piperazinyl]carbonyl]4,7- dihydro-N-(4- hydroxyphenyl)-5-methylpyrazolo[1,5- a]pyrimidine-2- carboxamide 621 446

1-[[7-(3,4-Dichloro- phenyl)-4,7dihydro-5- methyl-2-[[(2S)-2-(1-pyrrolidinylmethyl)-1- pyrrolidinyl]carbonyl]- pyrazolo[1,5-a]pyrimidin-6-yl]carbonyl]-4-(4- fluorophenyl)piperazine 666 447

7-(3,4-Dichlorophenyl)-6- [[4-(4-fluorophenyl)-1-piperazinyl]carbonyl]-4,7- dihydro-5- methylpyrazolo[1,5-a]pyrimidine-2- carboxamide 529 448

7-(3,4-Dichlorophenyl)-6- [[4-(4-fluorophenyl)-1-piperazinyl]carbonyl]-4,7- dihydro-5-methyl-N- phenylmethyl)pyrazolo-[1,5-a]pyrimidine-2- carboxamide 619 449

7-(3,4-Dichlorophenyl)-6- [[4-(4-fluorophenyl)-1-piperazinyl]carbonyl]-4,7- dihydro-5-methyl-N-(2-phenylethyl)-pyrazolo[1,5- a]pyri-midine-2- carboxamide 633

EXAMPLE 4501-[[2-Cyano-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl]carbonyl]-4-(4-fluorophenyl)piperazine

Method:

Compound 1: Compound 1 (the compound of Example 447) was prepared in amanner similar to that described in Example 443.

Title Compound: Triflic anhydride (0.036 mL, 0.21 mmol) was added to a0° C. solution of compound 1 (0.103 g, 0.19 mmol) and triethylamine(0.054 mL, 0.39 mmol) in dichloromethane (5 mL). After 10 min., TLC (5%methanol/ethyl acetate) indicated that compound 1 remained. AdditionalTriflic anhydride (0.036 mL, 0.21 mmol) and triethylamine (0.054 mL,0.39 mmol) were added. After 10 min., TLC (5% methanol/ethyl acetate)indicated that compound 1 remained. The mixture was warmed to roomtemperature and stirred for an additional 30 min. The reaction waspoured into saturated sodium bicarbonate, extracted withdichloromethane. The extracts were combined, dried over anhydrous sodiumsulfate and concentrated. The resulting residue was purified by silicagel chromatography eluting with 2% methanol/ethyl acetate to 0.018 g(19% yield) of the title compound as a white solid. Reverse phase LC/MS:YMC S5 4.6×33 column, UV detection at 220λ, 2 min gradient 0-100%Solvent B/A (Solvent A: 10% MeOH/H₂O with 0.1% TFA, Solvent B:-90%MeOH/H₂O with 0.1% TFA), 4 mL/min. Rt=3.60 min, 81% pure). MS (M+H:511).

EXAMPLE 4513-Bromo-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazolo[1,5-a]pyrimidine-6-carboxylicacid 1,1-dimethylethyl ester

Method:

Compound 1: Compound 1 was prepared as described in Example 4.

Title Compound: Phenyltrimethylammonium tribromide (0.057 g, 0.14 mmol)was added to a 0° C. solution of compound 1 (0.05 g, 0.13 mmol) indichloromethane (2 mL). The mixture was allowed to warm to roomtemperature over 4 h. The solvent was removed under reduced pressure.The resulting residue was purified by preparative TLC (Analtech, silicagel, 20×20 cm, 1000μ). Elution with 25% acetone/hexane provided 0.047 g(79% yield) of the title compound as a white solid. Reverse Phase HPLC:YMC S5 ODS 4.6×50 mm Ballistic column, UV detection at 220λ, 4 min.gradient 0-100% Solvent B/A (Solvent A: 10% MeOH/H₂O with 0.2% H₃PO₄,Solvent B: 90% MeOH/H₂O with 0.2% H₃PO₄), 4 mL/min. Rt=4.67 min, (95%pure). Reverse Phase LC/MS: YMC S5 ODS 4.6×50 mm Ballistic column, UVdetection at 220λ, 4 min. gradient 0-100% Solvent B/A (Solvent A: 10%MeOH/H₂O with 0.1% TFA, Solvent B: 90% MeOH/H₂O with 0.1% TFA), 4mL/min. Rt=4.19 min. MS (EM, M+1: 458) HMR (CDCl₃, 400MHz): 7.37(1H, d,J=2.0 Hz), 7.36(1H, d, J=8.0 Hz), 7.33(1H, s), 7.12(1H, dd, J=2.2 and8.4 Hz), 6.38(1H, s), 6.27(1H, s), 2.53(3H, s), 1.36(9H, s).

EXAMPLE 4521-[[3-Bromo-7-(2,3-dichlorophenyl)-4,7-dihydro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl]carbonyl]-4-phenylpiperazine

The compound of Example 452 was prepared in a manner similar to thatdescribed in Example 451. (M+H) 547.

EXAMPLE 4531-[[3-Chloro-7-(2,3-dichlorophenyl)-4,7-dihydro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl]carbonyl]-4-phenylpiperazine

Method:

Compound 1: Compound 1 was prepared in a manner similar to thatdescribed in Example 18, Method 2.

1Title Compound: N-chlorosuccinimide (0.0102 g, 0.076 mmol) was added toa 0° C. solution of compound 1 (0.0343 g, 0.073 mmol) in dichloromethane(4 mL). The mixture was allowed to warm to room temperature over 2 h.The solvent was removed under reduced pressure. The resulting residuewas purified by preparative TLC (Analtech, silica gel, 20×20 cm, 1000μ).Elution with 50% acetone/hexane provided 0.0287 g (77% yield) of thetitle compound as a yellow oil which solidified upon standing. ReversePhase HPLC: YMC S5 ODS 4.6×50 mm Ballistic column, UV detection at 220λ,4 min. gradient 0-100% Solvent B/A (Solvent A: 10% MeOH/H₂O with 0.2%PPA, Solvent B: 90% MeOH/H₂O with 0.2% PPA), 4 mL/min. Rt=4.21 min, (91%pure). Reverse Phase LC/MS: YMC S5 ODS 4.6×50 mm Ballistic column, UVdetection at 220λ, 4 min. gradient 0-100% Solvent B/A (Solvent A: 10%MeOH/H₂O with 0.1% TFA, Solvent B: 90% MeOH/H₂O with 0.1% TFA), 4mL/min. Rt=3.72 min. MS (EM, M+1: 501)

EXAMPLES 454-463

The compounds of Examples 454-463, shown in the table provided below,were prepared in a manner similar to that described in Example 453.

Example 456 was obtained from the single enantiomer B of Example 30, andExample 457 was obtained from the single enantiomer A of Example 29.Chiralpak AD column (4.6×250 mm) eluting with 30% isopropanol/hexanescontaining 0.1% triethylamine at 1 mL/min), UV detection at 254 □,Example 456 Rt==5.9 min, >99% ee. Example 457 Rt=6.3 min, >99% ee.

Example 458 was obtained from the single enantiomer A of Example 51, andExample 459 was obtained from the single enantiomer B of Example 52.Chiralcel OD column (4.6×250 mm) eluting with 30% isopropanol/hexanescontaining 0.1% triethylamine at 1 mL/min), UV detection at 254□,Example 458 Rt=7.8 min, >99% ee. Example 459 Rt=8.4 min, >99% ee.

Example 460 was obtained from the single enantiomer A of Example 169,and Example 461 was obtained from the single enantiomer B of Example168. Chiralpak AD column (4.6×250 mm) eluting with 20%isopropanol/hexanes containing 0.1% triethylamine at 1 mL/min), UVdetection at 254□, Example 461 Rt=9.2 min, >99% ee. Example 460 Rt=9.4min, >99% ee.

Example 462 was obtained from the single enantiomer A of Example 81, andExample 463 was obtained from the single enantiomer B of Example 82.Chiralpak AD column (4.6×250 mm) eluting with 20% isopropanol/hexanescontaining 0.1% triethylamine at 1 mL/min), UV detection at 254□,Example 462 Rt=8.25 min, >99% ee. Example 463 Rt=8.28 min, >99% ee.Example Structure Name (M + H) 454

1-[[3-Chloro-7-(2,3- dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-4-(4- fluorophenyl)piperazine520 455

1-[[3-Chloro-7-(3,4- dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-4-(4- fluorophenyl)piperazine520 456

1-[[3-Chloro-7-(2,3- dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-4- phenylpiperazine, enantiomerB 502 457

1-[[3-Chloro-7-(2,3- dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-4-phenyl- piperazine,enantiomer A 502 458

1-[[3-Chloro-7-(2,3- dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-4-(4- fluorophenyl)piperazine,enantiomer A 520 459

1-[[3-Chloro-7-(2,3- dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-4-(4- fluorophenyl)piperazine,enantiomer B 520 460

1-[[3-Chloro-7-(2,3- dichlorophenyl)-4,7- dihydro-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-4-(4- fluorophenyl)piperazine,enantiomer A 534 461

1-[[3-Chloro-7-(2,3- dichlorophenyl)-4,7- dihydro-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-4-(4- fluorophenyl)piperazine,enantiomer B 534 462

1-[[3-Chloro-7-(3,4- dichlorophenyl)-4,7- dihydro-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-4-(4- fluorophenyl)piperazine,enantiomer A 534 463

1-[[3-Chloro-7-(3,4- dichlorophenyl)-4,7- dihydro-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-4-(4- fluorophenyl)piperazine,enantiomer B 534

EXAMPLE 4643-Chloro-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazolo[1,5-a]pyrimidine-6-carboxylicacid 1,1-dimethylethyl ester

Method:

Compound 1: Compound 1 was prepared as described in Example 4.

Title Compound: Pyridine hydrochloride (0.020 g, 0.173 mmol) was addedto a 0° C. solution of compound 1 (0.060 g, 0.158 mmol) indichloromethane (4 mL). After 2 min, N-chlorosuccinimide (0.0231 g,0.174 mmol) was added. The mixture was allowed to warm to roomtemperature and was stirred for 13 h. The solvent was removed underreduced pressure. The resulting residue was purified by preparative TLC(Analtech, silica gel, 20×20 cm, 1000μ). Elution with 20% acetone/hexaneprovided 0.0092 g (14% yield) of the title compound as a yellow oil.Reverse Phase HPLC: YMC S5 ODS 4.6×50 mm Ballistic column, UV detectionat 220λ, 4 min. gradient 0-100% Solvent B/A (Solvent A: 10% MeOH/H₂Owith 0.2% PPA, Solvent B: 90% MeOH/H₂O with 0.2% PPA), 4 mL/min. Rt=4.61min, (94% pure). Reverse Phase LC/MS: YMC S5 ODS 4.6×50 mm Ballisticcolumn, UV detection at 220λ, 4 min. gradient 0-100% Solvent B/A(Solvent A: 10% MeOH/H₂O with 0.1% TFA, Solvent B: 90% MeOH/H₂O with0.1% TFA), 4 mL/min. Rt=4.71 min. MS (EM, M+1: 414). HMR (CDCl₃,400MHz): 7.37(1H, s), 7.36(1H, d, J=1.7 Hz), 7.36(1H, d, J=8.4 Hz),7.12(1H, dd, J=2.0 and 8.4 Hz), 6.45(1H, brs), 6.24(1H, s), 2.52(3H, s),1.36(9H, s).

EXAMPLE 4657-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-6-(5-phenyl-2-oxazolyl)pyrazolo[1,5-a]pyrimidine

Method:

Compound 1: Compound 1 was synthesized as described in Example 16.

Compound 3: Compound 1 (200 mg, 0.62 mmol) was suspended in 2 mL ofdichloromethane. Triethylamine (300 μL, 2.2 mmol) and2-aminoacetophenone 2 (116 mg, 0.68 mmol) were added followed bybromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrOP) (312 mg,0.68 mmol). All the solid dissolved upon addition of PyBrOP and thereaction was stirred for 4 hrs. The mixture was loaded onto silica geland purified by flash chromatography on silica gel eluted with 40%acetone, hexane to yield 106 mg (39%) of a pink solid. ¹H NMR (400 MHz,CDCl3) 44180-148-16; ¹H COSY (400 MHz, CD3OD); ¹³C NMR (100 MHz, CDCl₃);HPLC >99% at 4.0 min (YMC S5 ODS 4.6×50 mm column; 10-90% methanol,water with 0.2% phosphoric acid gradient over 4 min.; 4 mL/min.; uvdetection at 220 nm).

Title Compound: The amide 3 (100 mg, 0.22 mmol) was dissolved in 2 mLphosphorus oxychloride and heated to 112° for 2 h. The mixture was thenquenched onto ice and extracted with ethylacetate. The extracts weredried over magnesium sulfate, filtered and the solvent removed toprovide 339 mg of a brown oil. The oil was purified by flashchromatography on silica gel eluted with 20-40% acetone, hexane to yield50 mg (51%) of the title compound as a white powder. mp 229-231°; ¹H NMR(400 MHz, CD3OD); MS (ESI) m/z 423 (MH⁺); HPLC>99% at 4.7 min (YMC S5ODS 4.6×50 mm column; 10-90% methanol, water with 0.2% phosphoric acidgradient over 4 min. then hold at 90% methanol, water; 4 mL/ min.; uvdetection at 220 nm).

EXAMPLES 466-469

The compounds of Examples 466-473, shown in the table provided below,were prepared in a manner similar to that described in Example 465.Example Structure Name (M + H) 466

7-(3,4-Dichlorophenyl)- 4,7-dihydro-5-methyl-6-(5-phenyl-1,3,4-oxa-diazol-2- yl)pyrazolo[1,5- a]pyrimidine 424 467

6-(1H-Benzimidazol-2-yl)- 7-(3,4-dichloro-phenyl)- 4,7-dihydro-5-methylpyrazolo[1,5- a]pyrimidine 396 468

6-(2-Benzothiazolyl)-7- (3,4-dichlorophenyl)-4,7- dihydro-5-methyl-pyrazolo[1,5-a]pyri-midine 413 469

7-(3,4-Dichlorophenyl)- 4,7-dihydro-5-methyl-6-(1-methyl-1H-benzimi-dazol- 2-yl)pyrazolo[1,5- a]pyrimidine 410

EXAMPLE 4707-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-6-[5-(trifluoromethyl)-1-propyl-1H-benzimidazol-2-yl]pyrazolo[1,5-a]pyrimidine

Method:

Compound 2: To a solution of acid 1, prepared as described in Example16, (0.15 g, 0.463 mmol), 2-(n-propylamino)-5-trifluromethylaniline(0.141 g, 0.648 mmol) and DMAP (5 mg, cat.) EDCI (0.124 g, 0.0648 mmol)was added and the solution was stirred at room temperature for 2 hours.The reaction was treated with saturated sodium bicarbonate, the organicsolution was dried with magnesium sulfate and the solvent wasevaporated. The crude product 2 was used without further purification.

Title Compound: Compound 2 was dissolved in phosphorus oxychloride (4mL) and heated to 80° C. for 4 h. TLC indicated the reaction was notcomplete. Additional phosphorus oxychloride (2 mL) was added and themixture was heated for 2 h and then left to stand at room temperatureovernight. The mixture was then quenched onto ice, made basic withammonium hydroxide, and extracted with ethyl acetate. The extracts weredried over magnesium sulfate and concentrated. The crude product waspurified by preparative reversed phase chromatography (YMC PACK ODSA S320×100 mm column 50-100 methanol, water with 0.1% TFA gradient over 10min.; 20 mL/min.; uv detection at 220 nm.) The appropriate fractionswere evaporated, the residue was partitioned between saturated sodiumbicarbonate and ethyl acetate, the organic solution was dried and thesolvent was removed under vacuum giving the product (27 mg, 11.5%) as atan glass. [M+H]⁺ m/z 506; HPLC 91.1% at 4.6 min (YMC S5 ODS 4.6×50 mmcolumn; 10-90% methanol, water with 0.2% phosphoric acid gradient over 4min.; 4 mL/min.; uv detection at 220 nm).

EXAMPLES 471-482

The compounds of Examples 471-482, shown in the table provided below,were prepared in a manner similar to that described in Example 470.

HPLC resolution of Example 480, Chiralcel OD column (50×500 mm), elutingwith 25% isopropanol/hexanes containing 0.1% triethylamine at 50mL/min), UV detection at 254λ provided enantiomers A (Example 481) and B(Example 482). Analytical Chiralcel OD column (4.6×250 mm) eluting with25% isopropanol/hexanes containing 0.1% triethylamine at 1 mL/min), UVdetection at 254λ, enantiomer A Rt=7.2 min, >99% ee. Enantiomer BRt=10.0 min, >99% ee. Example Structure Name (M + H) 471

6-(5-Butyl-1,3,4- oxadiazol-2-yl)-7-(3,4- dichlorophenyl)- 4,7dihydro-5-methylpyrazolo[1,5- a]pyrimidine 404 472

1-[[7-(3,4-Dichloro- phenyl)-4,7-dihydro-5- methyl-6-(4-methyl-1H-benzimidazol-2-yl)pyra- zolo[1,5-a]pyrimidine 410 473

1-[[7-(2,3-Dichloro- phenyl)-4,7-dihydro-5- methyl-6-(1-methyl-1H-benzimidazol-2-yl)pyra- zolo[1,5-a]pyrimidine 410 474

7-(3,4-Dichlorophenyl)- 4,7-dihydro-6-(imidazo [1,5-a]pyridin-3-yl)-5-methylpyrazolo[1,5- a]pyrimidine 510 475

7-(3,4-Dichlorophenyl)-6- (1-ethyl-5-nitro-1H- benzimidazol-2-yl)-4,7-dihydro-5-methyl- pyrazolo[1,5-a]pyri-midine 469 476

6-[5-Chloro-1-(1- methylethyl)-1H- benzimidazol-2-yl]-7-(3,4-dichlorophenyl)-4,7- dihydro-5-methyl- pyrazolo[1,5-a]pyrimidine 472 477

6-(5-Chloro-1-ethyl-1H- benzimidazol-2-yl)-7-(3,4- dichlorophenyl)-4,7-dihydro-5-methyl- pyrazolo[1,5-a]pyri-midine 458 478

7-(3,4-Dichlorophenyl)-6- (5-fluoro-1-propyl-1H- benzimidazol-2-yl)-4,7-dihydro-5-methylpyra- zolo[1,5-a]pyrimidine  456.35 479

7-(3,4-Dichlorophenyl)- 4,7-dihydro-5-methyl-6-[1- (1-methylethyl)-5-(trifluoromethyl)-1H- benzimidazol-2- yl]pyrazolo[1,5- a]pyrimidine 506480

7-(3,4-Dichlorophenyl)-6- (5-fluoro-1-methyl-1H- benzimidazol-2-yl)-4,7-dihydro-5-methyl- pyrazolo[1,5-a]pyri-midine 428 481

7-(3,4-Dichlorophenyl)-6- (5-fluoro-1-methyl-1H- benzimidazol-2-yl)-4,7-dihydro-5-methyl- pyrazolo[1,5-a]pyri- midine, enantiomer A 428 482

7-(3,4-Dichlorophenyl)-6- (5-fluoro-1-methyl-1H- benzimidazol-2-yl)-4,7-dihydro-5-methyl- pyrazolo[1,5-a]pyri- midine, enantiomer B 428

EXAMPLE 4837-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-6-[1-(phenylmethyl)-1H-benzimidazol-2-yl]pyrazolo[1,5-a]pyrimidine

Method:

Compound 1: Prepared as described in Example 16.

Compound 2: Prepared from compound 1 and phenylenediamine in a mannersimilar to that described in Example 470.

Compound 3: A suspension of 2 (50 mg 0.121 mmol), NaHCO₃ (50 mg, 0.6mmol) and benzyl bromide (20 mg, 0.121 mmol) in DMPU (0.5 mL) wasstirred at room temp. overnight. Another equivalent of benzyl bromidewas added completing the reaction. The suspension was partitionedbetween water and ethyl acetate, the organic phase was dried (MgSO₄),and the solvent was evaporated. The residue was flash chromatographedthrough silica eluting with hexane-acetone 2:1 to provide either or bothof compounds 3 and 3* (exact structure was not determined) (24.8 mg,41%) as a white solid. Mp 135-140; [M+H]⁺ m/z 504; HPLC 100% at 4.4 min(YMC S5 ODS 4.6×50 mm column; 10-90% methanol, water with 0.2%phosphoric acid gradient over 4 min.; 4 mL/min.; uv detection at 220nm).

Title Compound: Compound(s) 3/3* was dissolved in phosphorus oxychloride(1.5 mL) and heated to 80° C. for 5 h. Heating was discontinued and themixture was left to stand at room temperature overnight. The mixture wasquenched onto ice, made basic with ammonium hydroxide, and extractedwith ethyl acetate. The extracts were dried over magnesium sulfate andconcentrated. The residue was purified by flash chromatography (silicagel, 50% acetone/hexanes) to give 6.6 mg of the title compound as a tansolid. Mp 225-230; [M+H]⁺ m/z 486; HPLC 100% at 3.8 min (YMC S5 ODS4.6×50 mm column; 10-90% methanol, water with 0.2% phosphoric acidgradient over 4 min.; 4 mL/min.; uv detection at 220 nm).

EXAMPLE 4847-(3,4-Dichlorophenyl)-4,7-dihydro-5-(methoxymethyl)-N-(2-pyridinylmethyl)pyrazolo[1,5-a]pyrimidine-6-carboxamide

Scheme:

Synthesis of 3: A solution of recrystallized (acetone, hexane)2,2-Dimethyl-1,3-dioxane-4,6-dione (1, 25.0 g, 173.5 mmol) indichloromethane (350 mL) was treated with pyridine (27.4 g, 346.9 mmol).The reaction mixture was cooled to −5.1° C. To this stirred solution wasadded a solution of methoxyacetyl chloride (2, 20.7 g, 190.8 mmol) indichloromethane (150 mL) over 50 mins., maintaining the reactiontemperature below 1.5° C. The reaction mixture turned orange and aprecipitate formed. The reaction mixture was allowed to warm to 17.5° C.over 40 mins. The reaction mixture turned maroon and the solidsdissolved. After TLC (100% ethyl acetate) showed the reaction wascomplete, the reaction was quenched with 3.7% aqueous hydrochloric acid(500 mL) and the aqueous layer was extracted with dichloromethane). Theorganic extracts were combined and washed with saturated aqueous sodiumchloride, dried over anhydrous magnesium sulfate, and filtered. Thesolvent was removed. The resulting oil was dried on high vacuum toconstant weight to give 3 (33.11 g) in 88.3% yield.

Synthesis of 4: To a solution of 3 (33.1 g, 153 mmol) in 100 mL oftoluene was added 2-methyl-2-propanol (100 mL, 1.05 mol) and thereaction was heated to reflux. After 1.5 h the reaction was concentratedto give 4 (30.2 g) in 100% yield.

Synthesis of 5: To the solution of β-ketoester 4 (30.2 g, 160.6 mmol) indimethylformamide (120 mL) was added 3,4 dichlorobenzaldehyde (28.13 g,160.6 mmol), followed by 3-aminopyrazole (14.7 g, 176.7 mmol), thensodium hydrogen carbonate (54 g, 642.6 mmol). The reaction mixture washeated at 70° C. for 48 hrs. The reaction mixture was then cooled to 35°C. and transferred into rapidly stirring water (1.5 L) at RT. Theresulting off-white solid was filtered. The filtered solid was slurriedin water (1 L) and filtered again. The wet cake (165 g) was dissolvedinto ethyl acetate (1 L), giving a two-phase mixture. The mixture waswashed with saturated aqueous sodium chloride (500 mL). The organiclayer was dried over anhydrous magnesium sulfate and filtered. Thesolvent was removed. The resulting crude material was purified by columnchromatography using 40% ethyl acetate in hexane as eluent to give 5(22.6 g, 34.3%) as a white powder.

Synthesis of 6: To a solution of dihydropyrimidine tert-butyl ester 5(10.13 g, 24.7 mmol) in dichloromethane (150 mL) was added a solution oftrimethylsilyltrifluoromethanesulfonate (11 g, 49.5 mmol) indichloromethane (11 mL). After 1 hr, hexane (300 mL) was added slowlyand the reaction was concentrated to 250 mL. The product formed a gumand supernatant was decanted. Hexane (250 mL) was added and the mixturewas allowed to stir for 1 hr. The gum had solidified and formed apowder. The supernatant was decanted again and another 250 mL of hexanewas added. The mixture was stirred for 10 min and filtered. Theresulting wet cake was washed with hexane (250 mL)) and a fine off-whitepowder 6 resulted which was allowed to suction dry.

Synthesis of 7: To a suspension of dihydropyrimidine acid 6 (100 mg,0.28 mmol) in dichloromethane (10 mL) was added EDCI (76 mg, 0.39 mmol),followed by a solution of 2-pyridylmethylamine (32.4 mg, 0.39 mmol) indichloromethane (1 mL). After 2.5 hrs, the reaction was concentrated todryness and the crude mixture was purified by silica gel chromatographyusing 10% methanol in dichloromethane as eluent to give the titlecompound (90 mg, 72.4%) as an off-white powder. Mass Spec m/z (M+Na)⁺466.

EXAMPLES 485-496

The following compounds were prepared by the methods described inExample 484. Ex. Mass Spec # Structure Name (m/z) 485

7-(2,3-Dichlorophenyl)-4,7-dihydro- 5-(methoxymethyl)-N-(2-pyridinylmethyl)pyrazolo[1,5- a]pyrimidine-6-carboxamide 444 (M + H)⁺486

1-[[7-(3,4-Dichlorophenyl)-4,7- dihydro-5- (methoxymethyl)pyrazolo[1,5-a]pyrimidin-6-yl]carbonyl]-2-(4- fluorophenyl)pyrrolidine 501 (M + H)⁺487

7-(3,4-Dichlorophenyl)-4,7-dihydro- 5-methoxymethyl-N-(3-phenylpropyl)pyrazolo[1,5- a]pyrimidine-6-carboxamide 471 (M + H)⁺ 488

1-[[7-(3,4-Dichlorophenyl)-4,7- dihydro-5- (methoxymethyl)pyrazolo[1,5-a]pyrimidin-6-yl]carbonyl]-4-(4- fluorophenyl)piperazine 516 (M + H)⁺489

1-[[7-(3,4-Dichlorophenyl)-4,7- dihydro-5- (methoxymethyl)pyrazolo[1,5-a]pyrimidin-6-yl]carbonyl]piperidine 421 (M + H)⁺ 490

(2S)-1-[[7-(3,4-Dichlorophenyl)-4,7- dihydro-5-(methoxymethyl)pyrazolo[1,5- a]pyrimidin-6-yl]carbonyl]-2-(methoxymethyl)pyrrolidine 451 (M + H)⁺ 491

7-(3,4-Dichlorophenyl)-4,7-dihydro- 5-(methoxymethyl)-N,N-dipropyl-pyrazolo[1,5-a]pyrimidine-6- carboxamide 437 (M + H)⁺ 492

5-Cyclohexyl-7-(3,4- dichlorophenyl)-4,7-dihydro-N-(3-phenylpropyl)pyrazolo[1,5- a]pyrimidine-6-carboxamide 509 (M + H)  493

1-[[5-Cyclohexyl-7-(3,4- dichlorophenyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-4-(4-fluorophenyl)piperazine 554 (M + H)  494

1-[[5-Cyclohexyl-7-(3,4- dichlorophenyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]piperidine 459 (M + H) 495

(2S)-1-[[5-Cyclohexyl-7-(3,4- dichlorophenyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]-2-(methoxymethyl)pyrrolidine 489 (M + H)  496

5-Cyclohexyl-7-(3,4- dichlorophenyl)-4,7-dihydro-N,N-dipropylpyrazolo[1,5-a]pyrimidine-6- carboxamide 475 (M + H) 

EXAMPLE 4977-(3,4-Dichlorophenyl)-4,7-dihydro-6-(imidazo[1,5-a]pyridin-3-yl)-5-(methoxymethyl)pyrazolo[1,5-a]pyrimidine

Synthesis of 1: The synthesis 1 was described in Example 484.

Synthesis of 2: The title compound was synthesized in a manner describedin Example 465. The product was purified by preparative TLC in 10%methanol in dichloromethane. Mass Spec m/z (M+H)⁺ 426.

EXAMPLE 4987-(2,3-Dichlorophenyl)-4,7-dihydro-6-(imidazo[1,5-a]pyridin-3-yl)-5-(methoxymethyl)pyrazolo[1,5-a]pyrimidine

The title compound was synthesized in a manner similar to that describedin Example 497. Mass Spec m/z (M+H)⁺ 426

EXAMPLE 4997-(3,4-Dichlorophenyl)-6-(5-fluoro-1-methyl-1H-benzimidazol-2-yl)-4,7-dihydro-5-(methoxymethyl)pyrazolo[1,5-a]pyrimidine

Starting with compound 6 from Example 484, the title compound wassynthesized in a manner similar to that described in Example 470. MassSpec m/z (M+H)⁺ 458. The title compound can be separated into purechiral form via preparative chiral HPLC (Chiralpak AD 5 cm×50 cm columneluted with 25% isopropanol in hexane with 0.1% TEA at 50 mL/min with UVdetection at 254 nM). The faster eluting isomer (example 503) isenantiomer A (HPLC retention time 6.8 min, 4.6×250 mm Chiralpak ADcolumn eluted with 25% isopropanol, hexane with 0.1% triethylamine at 1mL/min with UV detection at 220 nm) and the slower eluting isomer(example 504) is enantiomer B (HPLC retention time 12.0 min, 4.6×250 mmChiralpak AD column eluted with 25% isopropanol, hexane with 0.1%triethylamine at 1 mL/min with UV detection at 254 nm).

EXAMPLES 500-504

The following examples were synthesized by methods described in Example499: Ex. Structure Name Mass Spec 500

7-(2,3-Dichlorophenyl)-6-(4-fluoro- 1-methyl-1H-benzimidazol-2-yl)-4,7-dihydro-5- (methoxymethyl)pyrazolo[1,5- a]pyrimidine 458 (M + H)⁺ 501

7-(3,4-Dichlorophenyl)-6-(4-fluoro- 1-methyl-1H-benzimidazol-2-yl)-4,7-dihydro-5- (methoxymethyl)pyrazolo[1,5- a]pyrimidine 458 (M + H)⁺ 502

7-(2,3-Dichlorophenyl)-6-(5-fluoro- 1-methyl-1H-benzimidazol-2-yl)-4,7-dihydro-5- (methoxymethyl)pyrazolo[1,5- a]pyrimidine 458 (M + H)⁺ 503

7-(3,4-Dichlorophenyl)-6-(5-fluoro- 1-methyl-1H-benzimidazol-2-yl)-4,7-dihydro-5- (methoxymethyl)pyrazolo[1,5- a]pyrimidine enantiomer A 458(M + H)  504

7-(3,4-Dichlorophenyl)-6-(5-fluoro- 1-methyl-1H-benzimidazol-2-yl)-4,7-dihydro-5- (methoxymethyl)pyrazolo[1,5- a]pyrimidine enantiomer B 458(M + H) 

EXAMPLE 5057-(3,4-Dichlorophenyl)-4,7-dihydro-5-phenyl-N-(3-phenylpropyl)pyrazolo[1,5-a]pyrimidine-6-carboxamide

Synthesis of 1: A solution of benzoic acid (3.05 g, 25 mmol) intetrahydrofuran (25 mL) was treated with CDI (4.05 g, 25 mmol) atambient temperature. In a separate flask lithiumdiisopropylamide wasgenerated at −78° C. by treatment of a tetrahydrofuran solution (40 mL)of diisopropyl amine (10.6 mL, 76.0 mmol) with 2.5 M n-butyl lithium inhexanes (30 mL, 75.0 mmol). Tert-butyl acetate was added dropwise andthe reaction was stirred at −78° C. for 1 hr. The enolate wastransferred at −78° C. to a stirred solution of the imidazoylbenzoateprepared previously. The resulting solution was cooled to −78° C. Afterthe addition of the enolate was complete, a thick slurry resulted, whichwas broken up by shaking the reaction. The reaction mixture was allowedto stir for 1 h at −78° C. A 1N aqueous solution of hydrochloric acidwas added until the pH was 4. The reaction mixture was allowed to warmto ambient temperature with stirring. The reaction mixture was extractedwith diethyl ether. The combined organic layer was washed with aqueous1N hydrochloric acid, aqueous 10% sodium hydrogen carbonate, saturatedaqueous sodium chloride, dried over magnesium sulfate, and filtered. Thesolvent was removed to give 1 (5.0 g, 91%) as an oil.

Synthesis of 2: Compound 2 was synthesized in a manner similar to thatof compound 5 in example 484.

Synthesis of 3: Compound 3 was synthesized in a manner similar to thatof compound 6 in example 484.

Synthesis of 4: The title compound was synthesized in a manner similarto that of compound 7 in example 484. Mass Spec m/z (M+H)⁺ 503.

EXAMPLES 506-509

The following Examples 506-509 were synthesized in a manner similar tothat described in Example 505: Ex. Structure Name Mass Spec 506

1-[[7-(3,4-Dichlorophenyl)-4,7- dihydro-5-phenylpyrazolo[1,5-a]pyrimidin-6-yl]carbonyl]-4-(4- fluorophenyl)piperazine 448 (M + H)⁺507

1-[[7-(3,4-Dichlorophenyl)-4,7- dihydro-5-phenylpyrazolo[1,5-a]pyrimidin-6- yl]carbonyl]piperidine 459 (M + H)⁺ 508

(2S)-1-[[7-(3,4-Dichlorophenyl)- 4,7-dihydro-5-phenylpyrazolo[1,5-a]pyrimidin- 6-yl]carbonyl]-2-(methoxymethyl)pyrrolidine 483 (M + H)⁺ 509

7-(3,4-Dichlorophenyl)-4,7- dihydro-5-phenyl-N,N- dipropylpyrazolo[1,5-a]pyrimidine-6-carboxamide 475 (M + H) 

EXAMPLE 5101-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl]carbonyl]-2-phenylpyrazolidine

Preparation of 3: To a solution of dihydropyrimidine acid 1 (0.336 g, 1mmol) in dichloromethane (10 mL) was added 1-phenylpyrazolidine 2 (0.215g, 1.5 mmol, prepared using the procedure described in Tetrahedron,1973, 29, 4045) followed by1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.278 g,1.5 mmol) and the mixture stirred at room temperature for 2 hours. Thesolvent was evaporated and the residue purified by silica gelchromatography, eluting with ethyl acetate, to give the title compound 3(0.184 g, 39%) as a white powder. (M+H)⁺=455.

EXAMPLE 5116-(1-Chloro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-3-yl)-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazolo[1,5-a]pyrimidine

Preparation of B:: At 20° C., EDCI (100 mg, 0.52 mmol) was added to astirred slurry of carboxylic acid A (120 mg, 0.37 mmol) in CH₂Cl₂. After5 mins, proline amide was added (60 mg, 0.52 mmol) and the reactionmixture was stirred at ambient temperature for 3 h. The resulting yellowslurry was concentrated under reduced pressure, dissolved in 2 mLacetone and applied directly to a preparative silica gel TLC plate,(20×20 cm, 1 mm thickness, 254 nm UV indicator) eluting with 10% MeOH inCH₂Cl₂. The product B was isolated as a 1:1 ratio of diastereomers (79mg, 50% yield as a pale yellow glass.) HPLC: RT 2.61 and 2.80 min (YMCS5 ODS 4.6×50 mm Ballistic column) 10-90% MeOH/water with 0.2% PPAlinear gradient over 4 min, 4 mL/min, UV Detection at 220 nm. LCMS:R_(T)2.63 and 2.81 min (YMC S5 ODS 4.6×50 mm Ballistic column) 10-90%MeOH/water with 0.1% TFA linear gradient over 4 min, 4 mL/min, WVDetection at 220 nm, Mass Spec m/z (M+H)⁺ 420.

Preparation of C: Phosphorus oxychloride (4 mL) was added todiastereomers B (190 mg, 0.46 mmol). The slurry was heated to 100° C.for 12 h whereupon the precipitate dissolved furnishing an orangecolored solution. The cooled reaction mixture was poured cautiously intosaturated K₂CO₃ (ca. 20 mL) and extracted with EtOAc (3×30 mL). Thecombined organic portions were dried over Na₂SO₄, decanted andconcentrated yielding an orange oil which was purified directly bypreparative HPLC: R_(T)28.40 min (YMC S5 ODS 30×250 mm Reversed phaseC18 column) 30-90% MeOH/water with 0.1% TFA linear gradient over 30 min,25 mL/min, UV Detection at 220 nm. Product C (96 mg, 51% yield) wasobtained as a free base after removal of MeOH from the HPLC fractions,addition of 1.0M NaOH and extraction into CH₂Cl₂ (3×30 mL). Theenantiomers were separated by chiral preparative HPLC: R_(T)42.4 and59.0 min (ChiralPak OD 50×500 mm Normal phase column) 15% EtOH/hexaneIsocratic, 50 mL/min, UV Detection at 220 nm. Both enantiomers wereisolated as pale yellow powders, (34 mg of enantiomer A and 38 mgenantiomer B). Chiral HPLC Enantiomer B: R_(T)7.36 min (ChiralPak OD4.6×250 mm Normal phase column) 15% EtOH/hexane Isocratic, 2 mL/min, UVDetection at 220 nm 100% ee. Chiral HPLC Enantiomer A: R_(T)4.94 min(ChiralPak OD 4.6×250 mm Normal phase column) 15% EtOH/hexane Isocratic,2 mL/min, UV Detection at 220 nm 100% ee.

EXAMPLE 5127-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-6-(1-methyl-1H-thieno[3,4-d]imidazol-2-yl)pyrazolo[1,5-a]pyrimidine

Preparation of compound 1: as described in example 16.

Preparation of compound 2: To a suspension of the acid (152.9 mg, 0.47mmol) in 5 mL of anhydrous dichloromethane were addedtrichloroacetonitrile (57.0 μL, 0.67 mmol) and triphenylphosphine (186.2mg, 0.71 mmol). The mixture became clear and was allowed to stir at roomtemperature for 1 hour. The reaction mixture was transferred into asolution of 3,4-diaminothiophene hydrochloride (88.5 mg, 0.47 mmol) andtriethylamine (198.0 μL, 1.42 mmol) in 5 mL of dichloromethane. Thereaction was monitored using TLC or LC/MS. Upon completion of thecoupling, the reaction mixture was loaded directly onto silica gel andeluted with 5% methanol/dichloromethane to yield the desired amide as awhite solid (132.3 mg, 67%).

Preparation of compound 3: A suspension of the resulting amide (107 mg,0.25 mmol) and phosphorus pentachloride (53.1 mg, 0.25 mmol) inchloroform (20 mL) was heated to reflux under anhydrous argon for 5hours and the mixture was allowed to cool down to room temperature andstir overnight. Solvent was removed under reduced pressure, and theresidue was redissolved in ethyl acetate and briefly washed withsaturated aqueous sodium bicarbonate solution. The organic layer wasseparated, dried over sodium sulfate, and concentrated to give the crudethienoimidazole, which was purified by flash chromatograph using 100%ethyl acetate to give a brown solid (73 mg, 71%).

Preparation of compound 4: To a solution of the thienoimidazole (22.4mg, 0.06 mmol) in 2 mL of anhydrous DMF was added iodomethane (4.5 μL,0.07 mmol) and potassium carbonate (15.4 mg, 0.11 mmol). The mixture wasallowed to stir at room temperature overnight. The reaction was quenchedusing methanol. The mixture was diluted with ethyl acetate and washedwith 10% LiCl (3×10 mL) and brine (10 mL). The organic layer wasseparated and dried over sodium sulfate and concentrated to give aresidue, which was further purified using flash chromatograph (5%MeOH/ethyl acetate) and (6% MeOH/chloroform) to give the titled compoundas a white solid (4.5 mg, 20%).

EXAMPLE 5137-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-6-(4-methyl-4H-imidazo[3,4-d][1,2,5]thiadiazol-5-yl)pyrazolo[1,5-a]pyrimidine

Preparation of compound 5: To a suspension of the acid (120 mg, 0.37mmol) in 5 mL of anhydrous dichloromethane were addedtrichloroacetonitrile (55.9 μL, 0.56 mmol) and triphenylphosphine (146.2mg, 0.56 mmol). The mixture became clear and was allowed to stir at roomtemperature for 1 hour. The reaction mixture was transferred into asolution of 3,4-diamino-1,2,5-thiadiazole (51.7 mg, 0.45 mmol, preparedaccording to J. Heterocycl. Chem. 1976, 13, 13) and triethylamine (103.6μL, 0.74 mmol) in 5 mL of dichloromethane. The reaction was monitoredusing TLC or LC/MS. Upon completion of the coupling, the reactionmixture was loaded directly onto silica gel and eluted with 50% ethylacetate/hexanes to yield the desired amide as a yellow solid (56.4 mg,30%).

Preparation of compound 6: A suspension of the resulting amide (80 mg,0.19 mmol) and phosphorus pentachloride (79 mg, 0.38 mmol) in chloroform(10 mL) was stirred at room temperature under anhydrous argon for onehour and then heated to reflux for 2 hours. The mixture was allowed tocool down to room temperature and solvent was removed under reducedpressure. The residue was redissolved in ethyl acetate and brieflywashed with saturated aqueous sodium bicarbonate solution. The organiclayer was separated, dried over sodium sulfate, and concentrated to givethe crude thiodiazoimidazole, which was purified by flash chromatographusing 80% ethyl acetate/hexanes to give a yellow solid (29 mg, 38%).

Preparation of compound 7: To a solution of the thiadiazoimidazole (29mg, 0.07 mmol) in 2 mL of anhydrous DMF was added iodomethane (4.9 μL,0.08 mmol) and potassium carbonate (19.9 mg, 0.14 mmol). The mixture wasallowed to stir at room temperature under dry argon for 3 hours. Thereaction was quenched using methanol and diluted with ethyl acetate andwashed with 10% LiCl (3×10 mL) and brine (10 mL). The organic layer wasseparated and dried over sodium sulfate and concentrated to give aresidue, which was purified using HPLC to give the titled compound as awhite solid (1.6 mg, 5%).

EXAMPLE 5147-(3,4-Dichlorophenyl)-6-(1,6-dihydro-1,3,6-trimethylimidazo[4,5-c]pyrazol-5-yl)-4,7-dihydro-5-methylpyrazolo[1,5-a]pyrimidine

Preparation of compound 8: To a suspension of the acid (150 mg, 0.46mmol) in 5 mL of anhydrous dichloromethane were addedtrichloroacetonitrile (69.8 μL, 0.70 mmol) and triphenylphosphine (182.7mg, 0.70 mmol). The mixture became clear and was allowed to stir at roomtemperature for 1 hour. The reaction mixture was transferred into asolution of the diaminopyrazole (prepared according to J. Med. Chem.1995, 38, 3524) and triethylamine (129.5 μL, 0.93 mmol) in 5 mL ofdichloromethane. The reaction was monitored using TLC or LC/MS. Uponcompletion of the coupling, the reaction mixture was loaded directlyonto silica gel and eluted with 10% methanol/ethyl acetate to yield thedesired amide as a white solid.

Preparation of compound 9: A suspension of the resulting amide (39.5 mg,0.09 mmol) in phosphorus oxychloride (10 mL) was stirred at 80° C. underanhydrous argon overnight. The mixture was allowed to cool down to roomtemperature and solvent was removed under reduced pressure. The residuewas redissolved in ethyl acetate and briefly washed with saturatedaqueous sodium bicarbonate solution. The organic layer was separated,dried over sodium sulfate, and concentrated to give a residue, which waspurified by flash chromatograph using 10% methanol/dichloromethane togive the desired product as a light brown solid (13.9 mg, 37%).

EXAMPLE 5151-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-6-yl]carbonyl]-2-(2-thienyl)pyrrolidine

Preparation of compound 1: as described in example 17.

Preparation of compound 3: To a suspension of polystyrene supported HOBtreagent (5.2 g, 8.0 mmol) in 100 mL of anhydrous dichioromethane in areaction vessel that has a fritted glass filter at the bottom was addedthe acid (4.7 g, 12.0 mmol),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.3 g,12.0 mmol), and 4-dimethylaminopyridine (98 mg, 0.8 mmol). The mixturewas shook using an orbital shaker for 3 hours at room temperature.Solvent was drained through filtration, and the resin washed withanhydrous DMF (3×30 mL), anhydrous TF (3×30 mL), and anhydrousdichloromethane (3×30 mL). The resin that contains activated ester wasallowed to dry in vacuo overnight. The coupling yield was estimatedbased on the weight gain to be 84%.

Preparation of compound 4: Resin containing the HOBt-activated ester (58mg, 0.05 mmol) was distributed into a well, to which2-(2′-thienyl)-pyrrolidine (80 μL of 0.5 M, 0.04 mmol) was dispensed.The suspension was allowed to shake at room temperature for 3 hours, andthen polystyrene-supported isocyanate reagent was added (83 mg, 0.08mmol) and the suspension was shook for 2 hours. Solvent was collectedthrough filtration, and the resin was washed with dichloromethane (2×0.5mL). All filtrates were combined and concentrated under reduced pressureto give the desired product as a white solid (18 mg). The purity of theproduct was checked using LC/MS to be 100%, and m/z is 527.

EXAMPLES 516-587

The following compounds were synthesized using the procedure asdescribed in Example 515. Those compounds that have low purity werepurified using preparative HPLC to give the corresponding desiredproducts. Ex. Structure Name Mass Spec 516

1-[[7-(3,4-Dichlorophenyl)-4,7- dihydro-5-methyl-2-(trifluoromethyl)pyrazolo[1,5- a]pyrimidin-6-yl]carbonyl]-2-(4-methoxyphenyl)pyrrolidine 551 (M + H)⁺ 517

1-[[7-(3,4-Dichlorophenyl)-4,7- dihydro-5-methyl-2-(trifluoromethyl)pyrazolo[1,5- a]pyrimidin-6-yl]carbonyl]-2-(3-furanyl)pyrrolidine 511 (M + H)⁺ 518

1-[[7-(3,4-Dichlorophenyl)-4,7- dihydro-5-methyl-2-(trifluoromethyl)pyrazolo[1,5- a]pyrimidin-6-yl]carbonyl]-2-(2-pyridinyl)pyrrolidine 522 (M + H)⁺ 519

1-[[7-(3,4-Dichlorophenyl)-4,7- dihydro-5-methyl-2-(trifluoromethyl)pyrazolo[1,5- a]pyrimidin-6-yl]carbonyl]-2-(4-pyridinyl)pyrrolidine 522 (M + H)  520

1-[[7-(3,4-Dichlorophenyl)-4,7- dihydro-5-methyl-2-(trifluoromethyl)pyrazolo[1,5- a]pyrimidin-6-yl]carbonyl]-2-(phenylmethyl)pyrrolidine 535 (M + H)  521

1-[[7-(3,4-Dichlorophenyl)-4,7- dihydro-5-methyl-2-(trifluoromethyl)pyrazolo[1,5- a]pyrimidin-6-yl]carbonyl]-2-(2-methoxyphenyl)pyrrolidine 551 (M + H)  522

1-[[7-(3,4-Dichlorophenyl)-4,7- dihydro-5-methyl-2-(trifluoromethyl)pyrazolo[1,5- a]pyrimidin-6-yl]carbonyl]-2-(2-phenylethyl)pyrrolidine 549 (M + H)  523

7-(3,4-Dichlorophenyl)-N-(2,3- dimethylcyclohexyl)-4,7-dihydro-5-methyl-2- (trifluoromethyl)pyrazolo[1,5- a]pyrimidine-6-carboxamide 501(M + H)  524

7-(3,4-Dichlorophenyl)-4,7-dihydro- 5-methyl-N-[1-(1-naphthalenyl)ethyl]-2- (trifluoromethyl)pyrazolo[1,5-a]pyrimidine-6-carboxamide 545 (M + H)  525

7-(3,4-Dichlorophenyl)-4,7-dihydro- 5-methyl-N-[2-(1-piperidinyl)ethyl]-2-(trifluoromethyl)pyrazolo[1,5- a]pyrimidine-6-carboxamide 502 (M + H) 526

7-(3,4-Dichlorophenyl)-N-(2,2- diphenylethyl)-4,7-dihydro-5- methyl-2-(trifluoromethyl)pyrazolo[1,5- a]pyrimidine-6-carboxamide 571 (M + H) 527

N-[2-(1-Cyclohexen-1-yl)ethyl]-7- (3,4-dichlorophenyl)-4,7-dihydro-5-methyl-2- (trifluoromethyl)pyrazolo[1,5- a]pyrimidine-6-carboxamide 499(M + H)  528

7-(3,4-Dichlorophenyl)-4,7-dihydro- 5-methyl-N-[2-(phenylthio)ethyl]-2-trifluoromethyl)pyrazolo[1,5- a]pyrimidine-6-carboxamide 527 (M + H) 529

N-([1,1′-Bicyclohexyl]-2-yl)-7-(3,4- dichlorophenyl)-4,7-dihydro-5-methyl-2- (trifluoromethyl)pyrazolo[1,5- a]pyrimidine-6-carboxamide 555(M + H)  530

7-(3,4-Dichlorophenyl)-N-[2-[[(2,6- dichlorophenyl)methyl]thio]ethyl]-4,7-dihydro-5-methyl-2- (trifluoromethyl)pyrazolo[1,5-a]pyrimidine-6-carboxamide 610 (M + H)  531

N-[(2-Chloro-6- methylphenyl)methyl]-7-(3,4-dichlorophenyl)-4,7-dihydro-5- methyl-2- (trifluoromethyl)pyrazolo[1,5-a]pyrimidine-6-carboxamide 529 (M + H)  532

N-(Bicyclo[2.2.1]heptan-2-yl)-7- (3,4-dichlorophenyl)-4,7-dihydro-methyl-2- (trifluoromethyl)pyrazolo[1,5- a]pyrimidine-6-carboxamide 485(M + H)  533

N-Cyclobutyl-7-(3,4- dichlorophenyl)-4,7-dihydro-5- methyl-2-(trifluoromethyl)pyrazolo[1,5- a]pyrimidine-6-carboxamide 445 (M + H) 534

N-Cyclopentyl-7-(3,4- dichlorophenyl)-4,7-dihydro-5- methyl-2-(trifluoromethyl)pyrazolo[1,5- a]pyrimidine-6-carboxamide 458 (M + H) 535

N-Cyclohexyl-7-(3,4- dichlorophenyl)-4,7-dihydro-5- methyl-2-(trifluoromethyl)pyrazolo[1,5- a]pyrimidine-6-carboxamide 473 (M + H) 536

7-(3,4-Dichlorophenyl)-4,7-dihydro- 5-methyl-N-(2-methylcyclohexyl)-2-(trifluoromethyl)pyrazolo[1,5- a]pyrimidine-6-carboxamide 487 (M + H) 537

N-(Cyclohexylmethyl)-7-(3,4- dichlorophenyl)-4,7-dihydro-5- methyl-2-(trifluoromethyl)pyrazolo[1,5- a]pyrimidine-6-carboxamide 487 (M + H) 538

N-(2-Cyanoethyl)-7-(3,4- dichlorophenyl)-4,7-dihydro-N,5- dimethyl-2-(trifluoromethyl)pyrazolo[1,5- a]pyrimidine-6-carboxamide 458 (M + H) 539

7-(3,4-Dichlorophenyl)-4,7-dihydro- 5-methyl-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]-2- (trifluoromethyl)pyrazolo[1,5-a]pyrimidine-6-carboxamide 502 (M + H)  540

7-(3,4-Dichlorophenyl)-N-[(1-ethyl- 2-pyrrolidinyl)methyl]-4,7-dihydro-5-methyl-2- (trifluoromethyl)pyrazolo[1,5- a]pyrimidine-6-carboxamide502 (M + H)  541

7-(3,4-Dichlorophenyl)-4,7-dihydro- 5-methyl-N-[2-(1-pyrrolidinyl)ethyl]-2- (trifluoromethyl)pyrazolo[1,5-a]pyrimidine-6-carboxamide 488 (M + H)  542

N-Cyclohexyl-7-(3,4- dichlorophenyl)-N-ethyl-4,7- dihydro-5-methyl-2-(trifluoromethyl)pyrazolo[1,5- a]pyrimidine-6-carboxamide 501 (M + H) 543

N-Cycloheptyl-7-(3,4- dichlorophenyl)-4,7-dihydro-5- methyl-2-(trifluoromethyl)pyrazolo[1,5- a]pyrimidine -6-carboxamide 487 (M + H) 544

7-(3,4-Dichlorophenyl)-4,7-dihydro- [(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]-5-methyl-2- (trifluoromethyl)pyrazolo[1,5-a]pyrimidine-6-carboxamide 491 (M + H)  545

3-[[7-(3,4-Dichlorophenyl)- 4,7dihydro-5-methyl-2-(trifluoromethyl)pyrazolo[1,5- a]pyrimidin-6- yl]carbonyl]thiazolidine463 (M + H)  546

1-[[7-(3,4-Dichlorophenyl)- 4,7dihydro-5-methyl-2-(trifluoromethyl)pyrazolo[1,5- a]pyrimidin-6- yl]carbonyl]pyrrolidine445 (M + H)  547

7-(3,4-Dichlorophenyl)-4,7-dihydro- 5-methyl-N-(2-thienylmethyl)-2-(trifluoromethyl)pyrazolo[1,5- a]pyrimidine-6-carboxamide 487 (M + H) 548

1-[[7-(3,4-Dichlorophenyl)- 4,7dihydro-5-methyl-2-(trifluoromethyl)pyrazolo[1,5- a]pyrimidin-6-yl]carbonyl]-4-methylpiperazine 474 (M + H)  549

8-[[7-(3,4-Dichlorophenyl)- 4,7dihydro-5-methyl-2-(trifluoromethyl)pyrazolo[1,5- a]pyrimidin-6-yl]carbonyl]-1,4-dioxa-8-azaspiro[4.5]decane 517 (M + H)  550

1-[[7-(3,4-Dichlorophenyl)-4,7- dihydro-5-methyl-2-(trifluoromethyl)pyrazolo[1,5- a]pyrimidin-6-yl]carbonyl]-4-(phenylmethyl)piperidine 549 (M + H)  551

7-(3,4-Dichlorophenyl)-4,7-dihydro- 5-methyl-N-[4-(4-morpholinyl)phenyl]-2- (trifluoromethyl)pyrazolo[1,5-a]pyrimidine-6-carboxamide 552 (M + H)  552

7-(3,4-Dichlorophenyl)-4,7-dihydro- 5-methyl-N-[3-(4-morpholinyl)propyl]-2- (trifluoromethyl)pyrazolo[1,5-a]pyrimidine-6-carboxamide 518 (M + H)  553

7-(3,4-Dichlorophenyl)-4,7-dihydro- N,5-dimethyl-N-[2-(2-pyridinyl)ethyl]-2- (trifluoromethyl)pyrazolo[1,5-a]pyrimidine-6-carboxamide 510 (M + H)  554

7-(3,4-Dichlorophenyl)-N-(2,3- dihydro-1,4-benzodioxin-6-yl)-4,7-dihydro-5-methyl-2- (trifluoromethyl)pyrazolo[1,5-a]pyrimidine-6-carboxamide 525 (M + H)  555

7-(3,4-Dichlorophenyl)-4,7-dihydro- 5-methyl-N-(1-phenylethyl)-2-(trifluoromethyl)pyrazolo[1,5- a]pyrimidine-6-carboxamide 495 (M + H) 556

7-(3,4-Dichlorophenyl)-4,7-dihydro- 5-methyl-N-(1-methylpropyl)-2-(trifluoromethyl)pyrazolo[1,5- a]pyrimidine-6-carboxamide 447 (M + H) 557

7-(3,4-Dichlorophenyl)-4,7-dihydro- 5-methyl-N-(phenylmethyl)-2-(trifluoromethyl)pyrazolo[1,5- a]pyrimidine-6-carboxamide 481 (M + H) 558

7-(3,4-Dichlorophenyl)-N-[(2- fluorophenyl)methyl]-4,7-dihydro-5-methyl-2- (trifluoromethyl)pyrazolo[1,5- a]pyrimidine-6-carboxamide 499(M + H)  559

N-[(2-Chlorophenyl)methyl]-7-(3,4- dichlorophenyl)-4,7-dihydro-5-methyl-2- (trifluoromethyl)pyrazolo[1,5- a]pyrimidine-6-carboxamide 515(M + H)  560

7-(3,4-Dichlorophenyl)-N-[(4- fluorophenyl)methyl]-4,7-dihydro-5-methyl-2- (trifluoromethyl)pyrazolo[1,5- a]pyrimidine-6-carboxamide 499(M + H)  561

7-(3,4-Dichlorophenyl)-4,7-dihydro- 5-methyl-N-(2-phenylethyl)-2-(trifluoromethyl)pyrazolo[1,5- a]pyrimidine-6-carboxamide 495 (M + H) 562

N-[2-(4-Chlorophenyl)ethyl]-7-(3,4- dichlorophenyl)-4,7-dihydro-5-methyl-2- (trifluoromethyl)pyrazolo[1,5- a]pyrimidine-6-carboxamide 530(M + H)  563

7-(3,4-Dichlorophenyl)-4,7-dihydro- 5-methyl-N,N-bis(2-methylpropyl)-2-(trifluoromethyl)pyrazolo[1,5- a]pyrimidine-6-carboxamide 503 (M + H) 564

7-(3,4-Dichlorophenyl)-N-[(3,4- dichlorophenyl)methyl]-4,7-dihydro-N,5-dimethyl-2- (trifluoromethyl)pyrazolo[1,5-a]pyrimidine-6-carboxamide 564 (M + H)  565

N-[(2-Chlorophenyl)methyl]-7-(3,4- dichlorophenyl)-4,7-dihydro-N,5-dimethyl-2- (trifluoromethyl)pyrazolo[1,5- a]pyrimidine-6-carboxamide530 (M + H)  566

7-(3,4-Dichlorophenyl)-N-ethyl-4,7- dihydro-5-methyl-N-(1-methylethyl)-2- (trifluoromethyl)pyrazolo[1,5-a]pyrimidine-6-carboxamide 461 (M + H)  567

7-(3,4-Dichlorophenyl)-4,7-dihydro- 5-methyl-N-(phenylmethyl)-N-propyl-2- (trifluoromethyl)pyrazolo[1,5- a]pyrimidine-6-carboxamide 523(M + H)  568

7-(3,4-Dichlorophenyl)-4,7-dihydro- 5-methyl-N-[[4-(1-methylethyl)phenyl]methyl]-2- (trifluoromethyl)pyrazolo[1,5-a]pyrimidine-6-carboxamide 523 (M + H)  569

7-(3,4-Dichlorophenyl)-N-[2- [ethyl(3-methylphenyl)amino]ethyl]-4,7-dihydro-5-methyl-2- (trifluoromethyl)pyrazolo[1,5-a]pyrimidine-6-carboxamide 552 (M + H)  570

N-(Cyclopropylmethyl)-7-(3,4- dichlorophenyl)-4,7-dihydro-5- methyl-2-(trifluoromethyl)pyrazolo[1,5- a]pyrimidine-6-carboxamide 445 (M + H) 571

7-(3,4-Dichlorophenyl)-N-[2-(6- fluoro-1H-indol-3-yl)ethyl]-4,7-dihydro-5-methyl-2- (trifluoromethyl)pyrazolo[1,5-a]pyrimidine-6-carboxamide 552 (M + H)  572

N-[2-(Butylethylamino)ethyl]-7- (3,4-dichlorophenyl)-4,7-dihydro-5-methyl-2- (trifluoromethyl)pyrazolo[1,5- a]pyrimidine-6-carboxamide 518(M + H)  573

7-(3,4-Dichlorophenyl)-4,7-dihydro- 5-methyl-N-[1-(phenylmethyl)-3-pyrrolidinyl]-2- (trifluoromethyl)pyrazolo[1,5-a]pyrimidine-6-carboxamide 550 (M + H)  574

7-(3,4-Dichlorophenyl)-4,7-dihydro- 5-methyl-N-[[4-(trifluoromethyl)pyrazolo[1,5- a]pyrimidine-6-carboxamide 565 (M + H)575

7-(3,4-Dichlorophenyl)-4,7-dihydro- 5-methyl-N-[[3-(trifluoromethoxy)phenyl]methyl]-2- (trifluoromethyl)pyrazolo[1,5-a]pyrimidine-6-carboxamide 565 (M + H)  576

7-(3,4-Dichlorophenyl)-4,7-dihydro- 5-methyl-N-[(1R)-1-(1-naphthalenyl)ethyl]-2- (trifluoromethyl)pyrazolo[1,5-a]pyrimidine-6-carboxamide 545 (M + H)  577

7-(3,4-Dichlorophenyl)-4,7-dihydro- 5-methyl-N-[(1S)-1-(1-naphthalenyl)ethyl]-2- (trifluoromethyl)pyrazolo[1,5-a]pyrimidine-6-carboxamide 545 (M + H)  578

N-[(1S)-1-Cyclohexylethyl]-7-(3,4- dichlorophenyl)-4,7-dihydro-5-methyl-2- (trifluoromethyl)pyrazolo[1,5- a]pyrimidine-6-carboxamide 501(M + H)  579

7-(3,4-Dichlorophenyl)-4,7-dihydro- 5-methyl-N- (tricyclo[3.3.1.1 <3,7]decan-1- ylmethyl)-2- (trifluoromethyl)pyrazolo[1,5-a]pyrimidine-6-carboxamide 539 (M + H) 580

7-(3,4-Dichlorophenyl)-4,7-dihydro- 5-methyl-N-[(1R,2S,5R)-5-methyl-2-(1-methylethyl)cyclohexyl]-2- (trifluoromethyl)pyrazolo[1,5-a]pyrimidine-6-carboxamide 529 (M + H)  581

7-(3,4-Dichlorophenyl)-4,7-dihydro- 5-methyl-N-[2-(4-phenoxyphenyl)ethyl]-2- (trifluoromethyl)pyrazolo[1,5-a]pyrimidine-6-carboxamide 587 (M + H)  582

7-(3,4-Dichlorophenyl)-4,7-dihydro- 5-methyl-N-[[4-(1,2,3-thiadiazol-4-yl)phenyl]methyl]-2- (trifluoromethyl)pyrazolo[1,5-a]pyrimidine-6-carboxamide 565 (M + H)  583

7-(3,4-Dichlorophenyl)-4,7-dihydro- 5-methyl-N-(1-methyl-1-phenylethyl)-2- (trifluoromethyl)pyrazolo[1,5-a]pyrimidine-6-carboxamide 509 (M + H)  584

7-(3,4-Dichlorophenyl)-4,7-dihydro- 5-methyl-N-[(5-methyl-2-furanyl)methyl]-2- (trifluoromethyl)pyrazolo[1,5-a]pyrimidine-6-carboxamide 584 (M + H)  585

7-(3,4-Dichlorophenyl)-N-[[(2S)-1- ethyl-2-pyrrolidinyl]methyl]-4,7-dihydro-5-methyl-2- (trifluoromethyl)pyrazolo[1,5-a]pyrimidine-6-carboxamide 502 (M + H)  586

7-(3,4-Dichlorophenyl)-N-(4,6- dimethyl-2-pyridinyl)-4,7-dihydro-5-methyl-2- (trifluoromethyl)pyrazolo[1,5- a]pyrimidine-6-carboxamide596 (M + H)  587

7-(3,4-Dichlorophenyl)-N-(1,1- dimethylethyl)-4,7-dihydro-5- methyl-2-(trifluoromethyl)pyrazolo[1,5- a]pyrimidine-6-carboxamide 447 (M + H) 

EXAMPLE 5881-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl]carbonyl]-2-(3-methyl-1,2,4-oxadiazol-5-yl)pyrrolidine

Synthesis of 3: A mixture of N-(tert-butoxycarbonyl)-L-proline 1 (0.5 g,2.3 mmol), hydroxyamidine 2 (0.172 g, 2.3 mmol, prepared using theprocedure outlined in J. Fluor. Chem. 1999, 95, 127) and1-hydroxybenzotriazole hydrate (0.323 g, 2.4 mmol) in 22% dimethylformamide in dichloromethane (9 mL) was stirred at room temperature for0.5 hours. Then 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (0.757 g, 3.9 mmol) was added and the mixture stirredfurther at room temperature for 2 hours when HPLC indicated completionof the reaction. The reaction mixture was diluted with water andextracted with dichloromethane. The organic layers were washedsuccessively with saturated aqueous sodium bicarbonate solution,saturated aqueous sodium chloride solution and dried over magnesiumsulfate. Evaporation of the solvent provided a white solid with an(M+H)⁺ of 272 consistent for the coupled product 3.

Preparation of 4: The solid 3 was dissolved in tetrahydrofuran (17 mL),cesium carbonate (1.6 g) added and the mixture heated at 50-70° C. for18 hours after which HPLC indicated the complete consumption of 3. Thereaction was diluted with water and extracted with ethyl acetate. Theorganic layers were dried over magnesium sulfate and evaporated to givea light-green colored oil that had an (M+H)⁺ of 254 consistent with thedesired oxadiazole 4 which was used without any further purification.

Synthesis of 5: To a solution of 4 (0.288 g, 1.1 mmol) indichloromethane (9 mL) was added 0.9 mL of trifluoroacetic acid and thesolution stirred at room temperature for 18 hours when HPLC indicatedthe absence of 4. The reaction mixture was concentrated and the residuepurified by ion-exchange chromatography (using BioRad AG-50W-X2 resin,200-400 mesh, hydrogen form) eluting with 2N ammonia in methanol to givethe deprotected pyrrolidine 5 as an oil (0.122 g, 70%). (M+H)⁺=154

Synthesis of 6: To a solution of dihydropyrimidine acid (0.21 gram, 0.65mmol) in dichloromethane (10 mL) was added pyrrolidine 5 (0.139 gram,0.9 mmol) followed by 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (0.174 gram, 0.9 mmol) and the reaction stirred at roomtemperature for 1.5 hours. The solvent was evaporated and the residuepurified by silica gel chromatography, eluting with ethyl acetate, togive two diastereomers—a fast moving, less polar diastereomer-1 and aslow moving, more polar diastereomer-2, both as white amorphous solidswith an (M+H)⁺ of 460.

EXAMPLE 5891-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl]carbonyl]-2-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine

Synthesis of 4: A mixture of (+/−) N-(tert-butoxycarbonyl)-pipecolinicacid 1 (0.8 gram, 3.5 mmol), 1-hydroxybenzotriazole hydrate (1.14 gram,5.9 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (0.49 gram, 3.6 mmol) in 22% dimethyl formamide indichloromethane (20 mL) was stirred at room temperature for 0.5 hours.Then hydroxyamidine 2 (0.26 gram, 3.5 mmol, prepared using the procedureoutlined in J. Fluor. Chem. 1999, 95, 127) was added and the mixturestirred further at room temperature for 18 hours when HPLC indicatedcompletion of the reaction. The reaction mixture was diluted with waterand extracted with dichloromethane. The organic layers were washedsuccessively with saturated aqueous sodium bicarbonate solution,saturated aqueous sodium chloride solution and dried over magnesiumsulfate. Evaporation of the solvent provided a clear oil with an (M+H)⁺of 285 consistent for the coupled product 3. The oil 3 was dissolved intetrahydrofuran (25 mL), cesium carbonate (2.5 g) added and the mixtureheated at 50-70° C. for 18 hours after which HPLC indicated the completeconsumption of 3. The reaction was diluted with water and extracted withethyl acetate. The organic layers were dried over magnesium sulfate andevaporated to give a clear oil that had an (M+H)⁺ of 267 consistent withthe desired oxadiazole 4 which was used without any furtherpurification.

Synthesis of 5: To a solution of 4 (0.82 gram, 3.1 mmol) indichloromethane (20 mL) was added 2 mL of trifluoroacetic acid and thesolution stirred at room temperature for 18 hours when HPLC indicatedthe absence of 4. The reaction mixture was concentrated and the residuepurified by ion-exchange chromatography (using BioRad AG-50W-X2 resin,200-400 mesh, hydrogen form) eluting with 2N ammonia in methanol to givethe deprotected pyrrolidine 5 as an oil (0.46 gram, 89%). (M+H)⁺=167

Synthesis of title compound: To a solution of dihydropyrimidine acid(0.64 gram, 2.0 mmol) in dichloromethane (30 mL) was added pyrrolidine 5(0.462 gram, 2.8 mmol) followed by1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.53gram, 2.8 mmol) and the reaction stirred at room temperature for 2.5hours. The solvent was evaporated and the residue purified by silica gelchromatography, eluting with ethyl acetate, to give two diastereomers- aminor and less polar diastereomer (diastereomer 1) and a major morepolar diastereomer (diastereomer 2), both as white amorphous solids withan (M+H)⁺ of 473.

1. A compound of the formula I*

enantiomers, diasteriomers and pharmaceutically acceptable saltsthereof, wherein X¹, X² and X³, together with the atoms to which theyare bonded, form a ring selected from:

R¹, R², R⁵, R⁶ and R⁷ are independently selected from groups of theformula —(CH₂)_(n)-(Z¹)_(m)-(CH₂)_(p)-Z²; R⁴ is alkyl or substitutedalkyl; Z¹ is —CZ³Z⁴-, —O—, —NZ³-, —S—, —SO—, —SO₂—, —C(O)—, —C(O)Z³-,—C(O)NZ⁴, —C(S)—, —C(═NOZ³)-, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, carbocyclo,substituted carbocyclo, aryl, substituted aryl, heterocyclo, orsubstituted heterocyclo; Z² is hydrogen; —OZ⁵, —OC(O)Z⁵, —NZ⁵-C(O)-Z⁶,—NZ⁵-CO₂-Z⁶, —NZ⁵(C═O)—NZ⁶Z⁷, —NZ⁵Z⁶, —NO₂, halo, —CN, —C(O)Z⁵, —CO₂Z⁵,—C(S)Z⁵, —(C═NOZ⁵)Z⁶, —C(O)NZ⁵Z⁶, —C(S)NZ⁵Z⁶, —SZ⁵, —SOZ⁵, —SO₂Z⁵,—SO₂NZ⁵Z⁶, —CF₃, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, carbocyclo, substituted carbocyclo, aryl,substituted aryl, heterocyclo, or substituted heterocyclo; Z³, Z⁴, Z⁵,Z⁶ and Z⁷ are independently hydrogen, halo, alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carbocyclo,substituted carbocyclo, aryl, substituted aryl, heterocyclo, orsubstituted heterocyclo; or Z³, Z⁴, Z⁵, Z⁶ and Z⁷ may, in one or morepairs of two, together with the atoms to which they are bonded, form acarbocyclic, substituted carbocyclic, heterocyclic or substitutedheterocyclic group; R³* is —OZ⁵, —OC(O)-Z⁵, —NZ⁵-C(O)₂-Z⁶,—NZ⁵(C═O)—NZ⁶Z⁷, —NZ⁵Z⁶, —(C═NOZ⁵)Z⁶, —C(O)NZ⁵*Z⁶*, —C(S)NZ⁵*Z⁶*, —SZ⁵,—SOZ⁵, —SO²Z⁵, —SO₂NZ⁵Z⁶, —C(o)Z³*-Z²*, halo, alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carbocyclo,substituted carbocyclo, aryl, substituted aryl, heterocyclo orsubstituted heterocyclo, provided that when R^(3*) is —OC(O)-Z⁵, R⁷ isnot H, Me, cyclopentyl or F; Z²* is other than hydrogen when Z³* isheterocyclo; Z³* is heterocyclo or substituted heterocyclo; Z⁵* issubstituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, carbocyclo, substituted carbocyclo, aryl, substituted aryl,heterocyclo, or substituted heterocyclo; and Z⁶* is hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, carbocyclo, substituted carbocyclo, aryl, substituted aryl,heterocyclo, or substituted heterocyclo, provided that Z^(6*) is nothydrogen when Z^(5*) is unsubstituted cycloalkyl, unsubstituted aryl, orunsubstituted benzyl; or Z⁵* and Z⁶* may together with the nitrogen atomto which they are bonded form a heterocyclic group or substitutedheterocyclic group, provided that Z⁵* and Z⁶* do not together formunsubstituted piperidinyl, unsubstituted pyrrolidinyl, or unsubstitutedmorpholinyl; n and p are independently selected from integers from 0 to10 wherein, when m is 0, p is also 0; m is an integer selected from 0 or1; and q is an integer selected from 1 to 3; provided that said compoundis other than a compound of formula I where: R¹, R⁵, R⁶ and R⁷ areindependently selected from groups of the formula—(CH₂)_(n)-(Z¹)_(m)-(CH₂)_(p)-Z²; R² is phenyl or substituted phenyl; R⁴is alkyl or substituted alkyl; Z¹ is —CZ³Z⁴-, —O—, —NZ³-, —S—, —SO—,—SO₂—, —C(O)—, —C(O)Z³-, —C(O)NZ⁴, —C(S)—, —C(═NOZ³)-, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, carbocyclo, substituted carbocyclo, aryl, substituted aryl,heterocyclo, or substituted heterocyclo; Z² is hydrogen; —OZ⁵, —OC(O)Z⁵,—NZ⁵-C(O)-Z⁶, —NZ⁵-CO₂-Z⁶, —NZ⁵(C═O)—NZ⁶Z⁷, —NZ⁵Z⁶, —NO₂, halo, —CN,—C(O)Z⁵, —CO₂Z⁵, —C(S)Z⁵, —(C═NOZ⁵)Z⁶, —C(O)NZ⁵Z⁶, —C(S)NZ⁵Z⁶, —SZ⁵,—SOZ⁵, —SO₂Z⁵, —SO₂NZ⁵Z⁶, —CF₃, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, carbocyclo,substituted carbocyclo, aryl, substituted aryl, heterocyclo, orsubstituted heterocyclo; Z³, Z⁴, Z⁵, Z⁶ and Z⁷ are independentlyhydrogen, halo, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, carbocyclo, substituted carbocyclo, aryl,substituted aryl, heterocyclo, or substituted heterocyclo; or Z³, Z⁴,Z⁵, Z⁶ and Z⁷ may, in one or more pairs of two, together with the atomsto which they are bonded, form a carbocyclic, substituted carbocyclic,heterocyclic or substituted heterocyclic group; R³* is —C(O)NZ⁵*Z⁶*; Z⁵*and Z⁶* together with the nitrogen atom to which they are bonded form aheterocyclic group or substituted heterocyclic group, provided that Z⁵*and Z⁶* do not together form unsubstituted piperidinyl, substitutedpiperidinyl, unsubstituted pyrrolidinyl, or unsubstituted morpholinyl; nand p are independently selected from integers from 0 to 10 wherein,when m is 0, p is also 0; m is an integer selected from 0 or 1; and q isan integer selected from 1 to
 3. 2. A compound of claim 1 wherein R³* isheterocyclo; substituted heterocyclo; —C(O)NZ^(5*)Z^(6*),—C(O)Z³*⁻C(O)NZ⁵Z⁶, —C(O)Z^(3*)-CO₂Z⁵, —C(O)Z^(3*)-(aryl),—C(O)Z^(3*)-(substituted aryl), —C(O)Z^(3*)-(heterocyclo), orC(O)Z^(3*)-(substituted heterocyclo).
 3. A compound of claim 2 whereinR¹ is H; and R² is aryl, substituted aryl, heterocyclo, substitutedheterocyclo, carbocyclo or substituted carbocyclo.
 4. A compound ofclaim 1 wherein R^(3*) is heterocyclo or substituted heterocyclo.
 5. Acompound of claim 4 wherein R¹ is H; and R² is aryl, substituted aryl,heterocyclo, substituted heterocyclo, carbocyclo or substitutedcarbocyclo.
 6. A method of treating atrial arrhythmias comprisingadministering to a patient in need thereof an effective amount of atleast one compound of claim
 1. 7. A method of claim 6 wherein the atrialarrhythmia is atrial fibrillation.
 8. A method of claim 6 wherein theatrial arrhythmia is atrial flutter.
 9. A method of controlling heartrate comprising administering to a patient in need thereof an effectiveamount of at least one compound of claim
 1. 10. A method of treatinggastrointestinal disorders comprising administering to a patient in needthereof an effective amount of at least one compound of claim
 1. 11. Amethod of claim 10 wherein the gastrointestinal disorder is refluxesophagitis.
 12. A method of claim 10 wherein the gastrointestinaldisorder is a motility disorder.
 13. A method of treating inflammatoryor immunological disease comprising administering to a patient in needthereof an effective amount of at least one compound of claim
 1. 14. Amethod of claim 13 wherein the disease is chronic obstructive pulmonarydisease.
 15. A method of treating diabetes comprising administering to aperson in need thereof an effective amount of at least one compound ofclaim
 1. 16. A method of treating cognitive disorders comprisingadministering to a patient in need thereof an effective amount of atleast one compound of claim
 1. 17. A method of treating migrainecomprising administering to a patient in need thereof an effectiveamount of at least one compound of claim
 1. 18. A method of treatingepilepsy comprising administering to a patient in need thereof aneffective amount of at least one compound of claim
 1. 19. A method oftreating I_(kur)-associated conditions comprising administering to apatient in need thereof an effective amount of at least one compound ofclaim
 1. 20. A compound of claim 1, wherein R³* is —C(O)NZ⁵*Z⁶*.
 21. Apharmaceutical composition comprising at least one compound of claim 1in combination with one or more components selected from the groupconsisting of cyclooxygenase inhibitors, fibrinogen antagonists,diuretics, angiotensin converting enzyme inhibitors, angiotensin IIantagonists, thrombolytic agents, calcium channel blocking agents,thromboxane receptor antagonists, prostacyclin mimetics andphosphodiesterase inhibitors.
 22. A compound of claim 1 wherein R^(3*)is selected from


23. A compound of claim 1 wherein R⁷ is selected from alkyl, —CO₂alkyl,—CF₃, —CN, F or Cl.
 24. A compound of claim 1 wherein Z⁵* and Z⁶*together with the nitrogen atom to which they are bonded form aheterocyclic group or substituted heterocyclic group, provided that Z⁵*and Z⁶* do not together form unsubstituted piperidinyl, unsubstitutedpyrrolidinyl, or unsubstituted morpholinyl.
 25. A compound of claim 24wherein: R¹ is H; R² is aryl, substituted aryl, heterocyclo, substitutedheterocyclo, carbocyclo or substituted carbocyclo; R⁴ is alkyl orsubstituted alkyl; R⁵ is hydrogen, —(CH₂)_(n)-Z² wherein Z² is selectedfrom —C(O)NZ⁵Z⁶, —CO₂Z⁵, —NZ⁵Z⁶, aryl, substituted aryl, alkyl, orsubstituted alkyl; and R⁷ is selected from alkyl, —CO₂alkyl, —CF₃, —CN,F or Cl.
 26. A compound of claim 24 wherein: R¹ is H; R² is phenyl,substituted phenyl, heterocyclo, substituted heterocyclo, carbocyclo orsubstituted carbocyclo; R⁴ is lower alkyl, halo-substituted alkyl, oralkoxy-substituted alkyl; R⁵ is hydrogen, alkyl or substituted alkyl;and R⁷ is selected from alkyl, —CO₂alkyl, —CF₃, —CN, F or Cl.
 27. Acompound of claim 24 wherein: R¹ is H; R² is phenyl, substituted phenyl,heterocyclo, or substituted heterocyclo; R⁴ is lower alkyl,halo-substituted alkyl, or alkoxy-substituted alkyl; R⁵ is hydrogen,alkyl or substituted alkyl; and R⁷ is selected from alkyl, —CO₂alkyl,—CF₃, —CN, F or Cl.
 28. A compound of claim 24 wherein: R is H; R² issubstituted phenyl or substituted heterocyclo; R⁴ is lower alkyl oralkoxy-substituted alkyl; R⁵ is hydrogen, alkyl or substituted alkyl;and R⁷ is selected from alkyl, —CO₂alkyl, —CF₃, —CN, F or Cl.
 29. Apharmaceutical composition comprising a therapeutically effective amountof at least one compound of claim 1 and a pharmaceutically acceptablevehicle or carrier thereof.